간기능 검사의 해석!!

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Liver Function Tests

Vasimahmed Lala; Muhammad Zubair; David A. Minter.

Author Information and Affiliations

Last Update: July 30, 2023.

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Continuing Education Activity

The liver has a significant role in metabolism, digestion, detoxification, and elimination of substances from the body. The liver function tests typically include alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), the international normalized ratio (INR), total protein and albumin. These tests can help determine an area of the liver where damage may be taking place and, depending on the pattern of elevation, can help organize a differential diagnosis. Elevations in ALT and AST disproportion to elevations in alkaline phosphatase and bilirubin denote hepatocellular disease. An elevation in alkaline phosphatase and bilirubin in disproportion to ALT and AST would characterize a cholestatic pattern. The actual function of the liver can be graded based on its ability to produce albumin as well as vitamin K-dependent clotting factors.

평생 교육 활동

간은 

신진대사, 소화, 해독, 체내 물질 제거에 중요한 역할을 합니다. 

간 기능 검사에는 일반적으로 

알라닌 트랜스아미나제(ALT) 및 아스파테이트 트랜스아미나제(AST), 

알칼리성 포스파타제(ALP), 감

마-글루타밀 전이효소(GGT), 

혈청 빌리루빈, 

프로트롬빈 시간(PT), 

국제 정상화 비율(INR), 

총 단백질 및 알부민 등이 포함됩니다. 

alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), the international normalized ratio (INR), total protein and albumin

이러한 검사를 통해 

손상이 발생한 간 부위를 파악할 수 있으며, 

수치 상승 패턴에 따라 감별 진단을 내리는 데 도움이 될 수 있습니다. 

알칼리성 포스파타제 및 빌리루빈의 상승에 비례하여 

ALT 및 AST의 상승은 

간세포 질환을 나타냅니다. 

알칼리성 포스파타제 및 빌리루빈이 ALT 및 AST에 비해 불균형하게 상승하면 

담즙 정체 패턴의 특징이 됩니다. 

간의 실제 기능은 

알부민과 비타민 K 의존성 응고 인자를 생성하는 능력에 따라 

등급을 매길 수 있습니다.

Objectives:

•  
•  
•  
•  

• 비정상적인 간 기능 검사 결과의 가장 흔한 원인을 파악하십시오.
• 알코올성 간 질환에서 나타나는 간 기능 이상 패턴을 설명하십시오.
• 담즙 정체성 질환 환자에서 간 기능 검사 결과의 패턴을 설명하십시오.
• 간 기능 검사 패널에서 얻은 개별 검사의 의미를 요약하십시오.

Introduction

The liver, located in the right upper quadrant of the body and below the diaphragm, is responsible for several functions, including primary detoxification of various metabolites, synthesizing proteins, and producing digestive enzymes.[1]The liver also plays a significant role in metabolism, regulation of red blood cells (RBCs), and glucose synthesis and storage. Typically when reviewing liver function tests, the discussion includes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), 5'nucleotidase, total bilirubin, conjugated (direct) bilirubin, unconjugated (indirect)bilirubin, prothrombin time (PT), the international normalized ratio (INR), lactate dehydrogenase, total protein, globulins, and albumin. These tests can help determine the area of hepatic injury, and the elevation pattern can help organize a differential diagnosis.[2]

The term "liver function tests "is a misnomer as many of the tests do not comment on the function of the liver but rather pinpoint the source of the damage. Elevations in ALT and AST in out of proportion to ALP, and bilirubin denotes a hepatocellular disease. An elevation in  ALP and bilirubin in disproportion to ALT and AST would characterize a cholestatic pattern. A mixed injury pattern is defined as an elevation of alkaline phosphatase and AST/ALT levels. Isolated hyperbilirubinemia is defined as an elevation of bilirubin with normal alkaline phosphatase and AST/ALT levels.[3]The R ratio has been used to assess whether the pattern of liver injury is hepatocellular, cholestatic, or mixed. The R ratio is calculated by the formula R =(ALT value÷ALT ULN)÷(alkaline phosphatase value÷alkaline phosphatase ULN). An R ratio of >5 is defined as hepatocellular, <2 is cholestatic, and 2–5 is a mixed pattern.[4] The actual function of the liver can be graded based on its ability to produce albumin as well as vitamin K-dependent clotting factors.

소개

신체의 오른쪽 위 사분면과 횡격막 아래에 위치한

간은

다양한 대사물질의 1차 해독,

단백질 합성,

소화 효소 생산 등 여러 기능을 담당합니다.[1]

또한

간은

신진대사,

적혈구(RBC) 조절,

포도당 합성 및 저장에 중요한 역할을 담당합니다.

일반적으로

간 기능 검사를 검토할 때

알라닌 아미노전달효소(ALT), 아스파르테이트 아미노전달효소(AST), 알칼리성 포스파타제(ALP),

감마-글루타밀 전이효소(GGT), 5'뉴클레오티다제(5'nucleotidase),

총 빌리루빈, 공액(직접) 빌리루빈, 비공액(간접) 빌리루빈,

프로트롬빈 시간(PT), 국제 정상화 비율(INR), 젖산 탈수소효소, 총 단백질, 글로불린 및 알부민.

이러한 검사는

간 손상 부위를 파악하는 데 도움이 될 수 있으며, 수

치 상승 패턴은 감별 진단에 도움이 될 수 있습니다[2].

'간 기능 검사'라는 용어는 많은 검사가 간 기능에 대해 언급하지 않고 손상의 원인을 정확히 파악하기 때문에 잘못된 명칭입니다.

ALT와 AST의 상승은

ALP에 비례하지 않으며

빌리루빈은 간세포 질환을 나타냅니다.

ALP와 빌리루빈이 ALT 및 AST에 비해 불균형하게 상승하면

담즙 정체 패턴의 특징이 됩니다.

혼합 손상 패턴은

알칼리성 포스파타제 및 AST/ALT 수치가 상승하는 것으로 정의됩니다.

고립성 고빌리루빈혈증은 알칼리성 포스파타제 및 AST/ALT 수치가 정상인 빌리루빈의 상승으로 정의됩니다.[3]간 손상 패턴이 간세포성, 담즙 정체성 또는 혼합성인지 평가하기 위해 R 비를 사용했습니다. R 비율은 R =(ALT 값÷ALT ULN)÷(알칼리성 포스파타제 값÷알칼리성 포스파타제 ULN) 공식으로 계산합니다.

R 비율이 5를 초과하면 간세포성,

2 미만이면 담즙 정체성,

2~5는 혼합형으로 정의됩니다.[4]

간의 실제 기능은 알부민과 비타민 K 의존성 응고 인자를 생성하는 능력에 따라 등급을 매길 수 있습니다.

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Etiology and Epidemiology

Elevated liver function tests are found in approximately 8% of the general population. These elevations may be transient in patients without symptoms, with up to 30% of elevations resolving after three weeks. Thus, care should be taken when interpreting these results to avoid unnecessary testing.[5] A borderline AST and/or ALT elevation is defined as less than 2 times the upper limit of normal (ULN), a mild AST and/or ALT elevation as 2 to 5 times ULN, moderate AST and/or ALT elevation 5 to 15 times ULN, severe AST and/or ALT elevation greater than 15 times ULN, and massive AST and/or ALT greater than 10,000 IU/l.The magnitude of AST and ALT elevation varies depending on the cause of hepatocellular injury.[6]

원인 및 역학

간 기능 검사 수치 상승은 일반 인구의 약 8%에서 발견됩니다.

이러한 수치는 증상이 없는 환자에서 일시적으로 나타날 수 있으며,

30%이상 비정상으로 올라간 수치는

3주 후에 회복됩니다.

따라서 불필요한 검사를 피하기 위해 이러한 결과를 해석할 때 주의를 기울여야 합니다.[5]

경계성 AST 및/또는 ALT 상승은

정상 상한치(ULN)의 2배 미만,

경증 AST 및/또는 ALT 상승은 2~5배 ULN,

중등도 AST 및/또는 ALT 상승은 5~15배 ULN,

중증 AST 및/또는 ALT 상승은 15배 ULN 이상,

중증 ALT 상승은 1만 IU/l 이상으로 정의하고 있습니다.

AST 및 ALT 상승의 정도는

간세포 손상의 원인에 따라 다릅니다[6].

Differential Diagnosis Based on Elevated LFTs

Hepatocellular pattern: Elevated aminotransferases out of proportion to alkaline phosphatase

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•  

Cholestatic pattern: Elevated alkaline phosphatase +gamma glutamyl transferase + bilirubin out of proportion to AST and ALT

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•  

간수치 상승에 따른 감별 진단

간세포 패턴: 알칼리성 포스파타제에 비례하지 않는 아미노전달효소 상승

• ALT 우세: 급성 또는 만성 바이러스성 간염, 지방 간염, 급성 버드-키아리 증후군, 허혈성 간염, 자가 면역, 혈색소 침착증, 약물/독소, 자가 면역, 알파1-항트립신 결핍, 윌슨병, 셀리악병.

• AST 우세: 알코올 관련, 지방간염, 간경변, 비간성(용혈, 근육병증, 갑상선 질환, 운동)

담즙 정체 패턴: 알칼리성 포스파타제 + 감마 글루타밀 전이 효소 + 빌리루빈이 AST 및 ALT에 비례하여 상승했습니다.

• 간 담도 원인: 담관 폐쇄, 원발성 담즙성 간경변, 원발성 경화성 담관염, 약물에 의한 간 침윤성 질환(유육종증, 아밀로이드증, 림프종 등), 낭포성 섬유증, 간 전이, 담즙 정체증

• 간 이외의 원인: 뼈 질환, 임신, 만성 신부전, 림프종 또는 기타 악성 종양, 울혈성 심부전, 어린 시절 성장, 감염 또는 염증

Pathophysiology

Components of Liver Function Test

Hepatocellular Labs

Aminotransferase includes AST and ALT. They are markers of hepatocellular injury. They participate in gluconeogenesis by catalyzing the transfer of amino groups from aspartic acid or alanine to ketoglutaric acid to produce oxaloacetic acid and pyruvic acid, respectively. AST is present as cytosolic and mitochondrial isoenzymes and is found in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leucocytes, and red cells. It is not as sensitive or specific for the liver as ALT and elevation in AST may be seen as secondary to nonhepatic causes as well. AST activity in neonates and infants is approximately twice that in adults, but these decline to adult levels by approximately six months.[7]

ALT is a cytosolic enzyme that is found in high concentrations in the liver. The half-life of ALT is approximately 47 ± 10 hours. ALT is usually higher than AST in most types of liver disease in which the activity of both enzymes is predominantly from the hepatocyte cytosol. Hepatocellular injury and not necessarily cell death triggers the release of these enzymes into circulation. Both AST and ALT values are higher in normal males than females.[8]They also correlate with obesity with a normal reference range higher in those with higher body mass index.[9]

간세포 실험실

아미노전달효소에는

AST와 ALT가 포함됩니다.

이들은 간세포 손상의 마커입니다.

이들은 각각

아스파르트산 또는 알라닌에서 케토글루타르산으로 아미노기의 이동을 촉매하여

옥살로아세트산과 피루브산을 생성함으로써

포도당 생성에 참여합니다.

AST(GOT)는

세포질 및 미토콘드리아 동종 효소로 존재하며

간, 심장 근육, 골격근, 신장, 뇌, 췌장, 폐, 백혈구 및 적혈구에서 발견됩니다.

AST (Aspartate Aminotransferase), also known as GOT (Glutamate Oxaloacetate Transaminase),

AST는 ALT만큼 간에 민감하거나 특이적이지 않으며

AST의 상승은 간 이외의 원인에 의해

이차적으로 나타날 수도 있습니다.

신생아와 유아의 AST 활성도는

성인의 약 2배이지만,

약 6개월이 지나면 성인 수준으로 감소합니다[7].

ALT는

간에서 고농도로 발견되는 세포질 효소입니다.

ALT의 반감기는 약 47 ± 10시간입니다.

두 효소의 활성이

주로 간세포 세포질에서 발생하는 대부분의 간 질환에서

ALT는 일반적으로 AST보다 높습니다.

간세포 손상은

반드시 세포 사멸이 아니더라도

이러한 효소의 순환계 방출을 유발합니다.

AST와 ALT 수치는

모두 정상 남성이 여성보다 높습니다.[8]

또한

비만과도 상관관계가 있으며

체질량 지수가 높은 사람에서 정상 기준 범위보다 높습니다.[9]

Cholestasis Labs

Alkaline phosphatase is part of a family of zinc metalloenzymes that are highly concentrated in the microvilli of the bile canaliculus as well as several other tissues (e.g., bone, intestines, and placenta).[1] There are four isozymes: placental ALP or hPLALP (human placental ALP), germ cell ALP (GCALP or PLALP-like),  intestinal ALP (IALP), and tissue-nonspecific ALP (TNALP). Of these four, PLALP and GCALP are the most heat stable at 65 C, and the bone ALP component of TnALP is the least. In healthy, non-smoking individuals, the PLALP and GCALP represent less than 1% of total ALP activity in the serum.[10] 

A condition that can result in significantly increased plasma ALP is benign transient hyperphosphatasemia. Originally described in infants, transient hyperphosphatasemia can also occur in adults and during pregnancy. There is a marked rise in ALP, often to several thousand IU/L, which usually indicates significant pathology. It is, however, a benign condition with a return to normal of the ALP in 6 to 8 weeks. Transient hyperphosphatasaemia is associated with concurrent infections in over 60% of cases, particularly GIT infections. There is a characteristic pattern on polyacrylamide gel electrophoresis, with the normal pattern of isoenzymes being accompanied by variant forms that react with neuraminidase. It is believed to be due to changes in carbohydrate side chains causing failure of recognition by receptors and reduced clearance, thus prolonging half-life.[11] 

Glycoprotein gamma-glutamyltransferase (GGT) is located on membranes of cells with high secretory or absorptive activities. Its primary function is to catalyze the transfer of a gamma-glutamyl group from peptides to other amino acids. It is also abundant in many other sources of the body (kidney, pancreas, intestine, prostate, testicles, spleen, heart, and brain) but is more specific for biliary disease when compared to alkaline phosphatase because it is not present in bone. Serum GGT shows electrophoretic mobility and lectin-affinity reaction identical to the liver enzyme but different from GGT from the kidney, urine, and pancreas.GGT levels are reported to be increased by an average of 12-fold in obstructive liver disease compared to ALP, which increased only 3-fold, so GGT is slightly more sensitive than ALP in this regard.GGT activity level in children may be a reliable index of bile duct damage. It is a useful indicator in separating the two forms of idiopathic cholestasis, with or without bile duct involvement. In infants diagnosed with biliary atresia and managed surgically, the GGT levels stay high in the blood if the infant is breastfed. This is due to the high level of GGT in human breast milk for at least four weeks postpartum.[12] 

There is a relationship between plasma GGT activity and weight, with values being 50% higher in individuals with a BMI  greater than 30 kg/m2. This is believed to be due to fat deposition in the liver (steatosis) in obese subjects. Steatosis with a raised plasma GGT also occurs in diabetes mellitus, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. Any liver disease that results in fibrosis and/or cirrhosis, such as alcoholic cirrhosis, PBC, PSC, hemochromatosis, α1-antitrypsin deficiency, and Wilson disease, will cause a raised plasma GGT. Space-occupying lesions, including malignancy (HCC or metastases secondary to malignancy elsewhere in the body), and granulomatous disease, for example, sarcoidosis and TB, are also associated with a raised plasma GGT.5′-Nucleotidase (5′NT) is associated with the canalicular and sinusoidal plasma membranes. Its function is undefined. 5′NT is also found in the intestine, brain, heart, blood vessels, and endocrine pancreas. Serum levels of 5′NT are unaffected by sex or race, but age affects the level; values are lowest in children and increase gradually, reaching a plateau at approximately age 50 years. As with GGT, the primary role of the serum 5′NT level is to identify the organ source of an isolated serum alkaline phosphatase elevation. The 5′NT level is not increased in bone disease but primarily in hepatobiliary disease. LDH is commonly included in biochemical liver panels but has poor diagnostic specificity for liver disease. Markedly increased LDH levels are observed in hepatocellular necrosis, shock liver, lymphoma, or hemolysis associated with liver disease.[13] 

Bilirubin is the end product of heme catabolism, with 80% derived from hemoglobin. Unconjugated bilirubin is transported to the liver loosely bound to albumin. Bilirubin is water-insoluble and cannot be excreted in the urine. Bilirubin that is conjugated is water-soluble and appears in the urine. It is conjugated in the liver to bilirubin glucuronide and subsequently secreted into bile and the gut, respectively.[14]

담즙 정체 연구실

알칼리성 포스파타제는

담관의 미세 융모와 다른 여러 조직(예: 뼈, 장, 태반)에 고농도로 존재하는

아연 금속 효소 계열의 일부입니다.[1]

태반 ALP 또는 hPLALP(인간 태반 ALP),

생식세포 ALP(GCALP 또는 PLALP 유사),

장 ALP(IALP) 및 조직 비특이적 ALP(TNALP) 등 네 가지 이소자임이 존재합니다.

이 네 가지 중 PLALP와 GCALP가 65°C에서 가장 열에 안정적이며, TnALP의 뼈 ALP 성분이 가장 낮습니다. 건강한 비흡연자의 경우, 혈청 내 총 ALP 활성의 1% 미만을 차지합니다[10].

혈장 ALP가 현저하게 증가할 수 있는 질환은

양성 일과성 고인산혈증입니다.

일과성 고인산혈증은 원래 유아에게 나타나는 질환이지만, 성인과 임신 중에도 발생할 수 있습니다. ALP가 수천 IU/L까지 현저하게 상승하는 경우가 많으며, 이는 일반적으로 심각한 병리를 나타냅니다. 그러나 6~8주 이내에 정상으로 회복되는 양성 질환입니다. 일시적 고인산혈증은 60% 이상의 사례에서 동시 감염, 특히 위장관 감염과 관련이 있습니다. 폴리 아크릴 아미드 겔 전기 영동에는 특징적인 패턴이 있으며, 이소 효소의 정상적인 패턴에는 뉴라미니다아제와 반응하는 변종 형태가 동반됩니다. 이는 탄수화물 측쇄의 변화로 인해 수용체에 의한 인식이 실패하고 제거율이 감소하여 반감기가 연장되기 때문인 것으로 추정됩니다[11].

당단백질 감마 글루타밀 트랜스퍼라제(GGT)는 분비 또는 흡수 활성이 높은 세포막에 위치합니다. 주요 기능은 펩타이드에서 다른 아미노산으로 감마-글루타밀기를 옮기는 것을 촉매하는 것입니다. 또한 신장, 췌장, 장, 전립선, 고환, 비장, 심장, 뇌 등 신체의 다른 많은 기관에도 풍부하지만 뼈에는 존재하지 않기 때문에 알칼리성 포스파타제에 비해 담도 질환에 더 특이적입니다. 혈청 GGT는 간 효소와 동일한 전기영동성과 렉틴친화반응을 보이지만 신장, 소변, 췌장에서 나오는 GGT와는 다른 양상을 보이며, 폐쇄성 간질환에서는 평균 12배 정도 증가하는 것으로 보고되어 3배 정도만 증가하는 ALP에 비해 GGT는 이 점에서 ALP보다 약간 더 민감하며, 소아에서 GGT 활성도는 담관 손상의 신뢰할 수 있는 지표가 될 수 있습니다. 담관 침범 유무에 관계없이 두 가지 형태의 특발성 담즙 정체증을 구분하는 데 유용한 지표입니다. 담도 폐쇄증 진단을 받고 수술로 관리되는 영아의 경우 모유 수유를 하는 경우 혈중 GGT 수치가 높게 유지됩니다. 이는 산후 최소 4주 동안 모유에 GGT 수치가 높기 때문입니다[12].

혈장 GGT 활성도와 체중 사이에는 관계가 있으며, BMI가 30kg/㎡ 이상인 사람의 경우 수치가 50% 더 높습니다. 이는 비만인 경우 간에 지방이 축적(지방증)되기 때문인 것으로 추정됩니다. 혈장 GGT가 상승하는 지방증은 당뇨병, 비알코올성 지방간염, 비알코올성 지방간 질환에서도 발생합니다. 알코올성 간경변, 간경변성 간경변증, 간경변성 간세포암, 혈색소 침착증, α1-항트립신 결핍증, 윌슨병 등 섬유화 및/또는 간경변을 초래하는 모든 간 질환은 혈장 GGT 상승을 일으킵니다. 악성 종양(간세포암 또는 신체 다른 부위의 악성 종양으로 인한 이차 전이)과 육아종성 질환(예: 유육종증 및 결핵)을 포함한 공간 점유성 병변도 혈장 GGT 상승과 관련이 있습니다.5′-Nucleotidase(5′NT)는 관형 및 사인곡선형 혈장막과 관련이 있습니다. 그 기능은 정의되지 않았습니다. 5′NT는 장, 뇌, 심장, 혈관 및 내분비 췌장에서도 발견됩니다. 5′NT의 혈청 수치는 성별이나 인종에 영향을 받지 않지만, 연령은 수치에 영향을 미치며, 소아에서 가장 낮고 점차 증가하여 약 50세에 정점에 도달합니다. GGT와 마찬가지로, 혈청 5′NT 수치의 주요 역할은 분리된 혈청 알칼리성 포스파타제 상승의 장기 출처를 식별하는 것입니다. 5′NT 수치는 뼈 질환에서는 증가하지 않지만 주로 간 담도 질환에서 증가합니다. LDH는 일반적으로 생화학적 간 패널에 포함되지만 간 질환에 대한 진단 특이성이 낮습니다. 간세포 괴사, 쇼크성 간, 림프종 또는 간 질환과 관련된 용혈에서 현저하게 증가된 LDH 수치가 관찰됩니다[13].

빌리루빈은 헤모글로빈에서 80%가 파생되는 헴 이화 작용의 최종 산물입니다. 비공액 빌리루빈은 알부민에 느슨하게 결합된 상태로 간으로 운반됩니다. 빌리루빈은 수분이 녹지 않아 소변으로 배출되지 않습니다. 공액화된 빌리루빈은 수용성이며 소변에 나타납니다. 간에서 빌리루빈 글루쿠로니드로 접합된 후 담즙과 장으로 각각 분비됩니다[14].

Synthetic Function Tests

Albumin is synthesized by the hepatic parenchymal cells at a rate dependent on colloidal osmotic pressure and dietary protein intake. The rate of albumin synthesis is also subject to feedback regulation determined by the plasma albumin concentration. Maintenance of plasma albumin concentrations can be achieved with only 10% of normal hepatocyte mass. The half-life of albumin is 21 days. Traces of albumin can be found in almost all extracellular body fluids. Little is lost from the body by excretion.[15] It is catabolized in various tissues, which are taken up by cells by pinocytosis. Its constituent amino acids are released by intracellular proteolysis and returned to the body pool. With any liver disease, there is a fall in serum albumin, reflecting decreased synthesis. If liver function is normal and serum albumin is low, this may reflect poor protein intake (malnutrition) or protein loss (nephrotic syndrome, malabsorption, or protein-losing enteropathy).[16]

Prothrombin time (PT) measures the rate of conversion of prothrombin to thrombin. Except for factor VIII, all other coagulation factors are synthesized by the liver. Prothrombin time requires factors II, V, VII, and X, and, as these are made in the liver, the liver's function is crucial in coagulation. Suppose the synthetic function of the liver is normal and prothrombin time is delayed. This may indicate treatment with warfarin, consumptive coagulopathy (eg, disseminated intravascular coagulopathy), or vitamin K deficiency.[17]

합성 기능 검사

알부민은

간 실질 세포에서 콜로이드 삼투압과 식

이 단백질 섭취에 따라 달라지는 속도로 합성됩니다.

알부민 합성 속도는

혈장 알부민 농도에 의해 결정되는

피드백 조절의 영향을 받기도 합니다. 혈

장 알부민 농도의 유지는

정상 간세포 질량의 10%만 섭취해도 달성할 수 있습니다.

알부민의 반감기는

21일입니다.

알부민은

거의 모든 세포 외 체액에서 미량의 알부민이 발견될 수 있습니다.

배설에 의해 몸에서 손실되는 양은 거의 없습니다.[15]

그것은 다양한 조직에서 이화되어 피노 세포증에 의해 세포에 흡수됩니다.

그 구성 아미노산은 세포 내 단백질 분해에 의해 방출되어 체액으로 돌아갑니다.

간 질환이 있으면

혈청 알부민 수치가 감소하여

합성 감소를 반영합니다.

간 기능이 정상이고

혈청 알부민이 낮은 경우 단백질 섭취 부족(영양실조) 또는

단백질 손실(신증후군, 흡수 장애 또는 단백질 손실성 장병증)을 반영할 수 있습니다[16].

프로트롬빈 시간(PT)은

프로트롬빈이 트롬빈으로 전환되는 속도를 측정합니다.

제8인자를 제외한 다른 모든 응고 인자는

간에서 합성됩니다.

프로트롬빈 시간에는 인자 II, V, VII, X가 필요하며,

이들은 간에서 만들어지기 때문에

간 기능이 응고에 매우 중요합니다.

간의 합성 기능이 정상인데

프로트롬빈 시간이 지연된다고 가정해 보겠습니다.

이는

와파린, 소모성 응고병증(예: 파종성 혈관 내 응고병증) 또는

비타민 K 결핍으로 인한 치료를 의미할 수 있습니다[17].

Serological Tests

Liver-related autoantibodies are crucial for correctly diagnosing and classifying autoimmune liver diseases, namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). AIH-2 is specified by antibody to liver kidney microsomal antigen type-1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1). SMA, ANA, and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.[18]PBC is specified by antimitochondrial antibodies (AMA) reacting with enzymes of the 2-oxo-acid dehydrogenase complexes (chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly reacting with nuclear pore gp210 and nuclear body sp100. Sclerosing cholangitis presents in at least two variants; first, the classical primary sclerosing cholangitis (PSC) mostly affects adult men wherein the only (and non-specific) reactivity is an atypical perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA), also termed perinuclear anti-neutrophil nuclear antibodies (p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis (ASC) with serological features resembling those of type 1 AIH.[19]

혈청학적 검사

간 관련 자가 항체는

자가 면역성 간 질환,

즉 자가 면역성 간염 1형 및 2형(AIH-1 및 2형),

원발성 담즙성 간경변증(PBC),

성인과 어린이의 경화성 담관염 변종을 정확하게 진단하고 분류하는 데 중요합니다.

AIH-1은 항핵항체(ANA)와 평활근 항체(SMA)로 지정됩니다. AIH-2는 간 신장 마이크로솜 항원 1형(항-LKM1) 및 항간 사이토솔 1형(항-LC1)에 대한 항체로 지정됩니다. SMA, ANA 및 항-LKM 항체는 간 이식 후 신생 AIH에 존재할 수 있습니다.[18]PBC는 2-옥소산 탈수소효소 복합체(주로 피루브산 탈수소효소 복합체 E2 서브 유닛)의 효소와 반응하는 항미토콘드리아 항체(AMA)와 주로 핵 기공 gp210 및 핵체 sp100과 반응하는 질병 특이적 ANA에 의해 지정됩니다. 경화성 담관염은 적어도 두 가지 변종으로 나타나는데, 첫째, 고전적인 원발성 경화성 담관염(PSC)은 주로 성인 남성에게 영향을 미치며 유일한(그리고 비특이적인) 반응성은 비정형 핵 주위 항 호중구 세포질 항체(p-ANNA)라고도 하는 핵 주위 항 호중구 핵 항체이며, 둘째는 1형 AIH와 유사한 혈청학적 특징을 가진 자가 면역 경화 담관염(ASC)이라는 소아기 질환입니다. [19]

Secondary Biochemical Liver Tests

Alpha-fetoprotein (AFP) measurements are used as a tumor marker for the detection and monitoring of primary hepatocellular malignancies, such as hepatoblastoma and HCC. Hepatoblasts produce alpha-fetoprotein, which is why it is raised in the regenerating liver, particularly in chronic viral hepatitis.[20]

Carbohydrate deficient transferrin is a high-specificity test for detecting excess alcohol intake as a cause of liver damage. The carbohydrate antigen CA19-9 is useful in monitoring the activity of the autoimmune disease PSC, which often progresses to a tumor of the bile ducts or cholangiocarcinoma.[21] Measurement of serum ferritin can be useful in identifying hemochromatosis, but ferritin is a positive acute phase reactant, so it is raised in many illnesses as well as being released from damaged hepatocytes in acute hepatic failure.[22]

이차 생화학 간 검사

알파 태아 단백질 (AFP) 측정은

간세포종 및 간세포암과 같은 원발성 간세포 악성 종양의 검출 및 모니터링을 위한 종양 마커로 사용됩니다.

간세포는

알파 태아 단백질을 생성하므로

재생 중인 간, 특히 만성 바이러스성 간염에서

알파 태아 단백질이 증가합니다[20].

탄수화물 결핍 트랜스페린은 간 손상의 원인으로 과도한 알코올 섭취를 감지하는 고 특이도 검사입니다. 탄수화물 항원 CA19-9는 종종 담관 종양이나 담관암으로 진행되는자가 면역 질환 PSC의 활동을 모니터링하는 데 유용합니다.[21] 혈청 페리틴 측정은 혈색소 침착증을 확인하는 데 유용 할 수 있지만 페리틴은 양성 급성기 반응물이기 때문에 급성 간부전의 손상된 간세포에서 방출 될뿐만 아니라 많은 질병에서 증가합니다.[22]

Specimen Requirements and Procedure

The serum is the specimen of choice. Consider all plasma or serum specimens potentially positive for infectious agents, including HIV and the hepatitis B virus. All specimens should be handled with standard precautions and sent to the lab immediately for processing. Separated serum or plasma should not remain at +15 C to +30 C longer than 8 hours. If assays are not completed within 8 hours, serum or plasma should be stored at +2 C to +8 C. If assays are not completed within 48 hours, or the separated sample is to be stored beyond 48 hours, samples should be frozen at –15 C to –20 C. Frozen samples should be thawed only once. Analyte deterioration may occur in samples that are repeatedly frozen and thawed.[23]

검체 요구 사항 및 절차

혈청을 검체로 선택합니다. 모든 혈장 또는 혈청 검체는 HIV 및 B형 간염 바이러스를 포함한 감염원에 양성일 가능성이 있는 것으로 간주합니다. 모든 검체는 표준 예방 조치에 따라 취급하고 즉시 실험실로 보내 처리해야 합니다. 분리된 혈청 또는 혈장은 +15°C ~ +30°C에서 8시간 이상 보관하지 않아야 합니다. 8시간 이내에 분석이 완료되지 않으면 혈청 또는 혈장을 +2°C~+8°C에서 보관해야 합니다. 48시간 이내에 분석이 완료되지 않거나 분리된 샘플을 48시간 이상 보관해야 하는 경우, 샘플을 -15°C~20°C에서 냉동해야 하며 냉동된 샘플은 한 번만 해동해야 합니다. 냉동과 해동을 반복하는 시료에서는 분석 물질의 열화가 발생할 수 있습니다[23].

Testing Procedures

Liver function tests are performed on semi-automatic or fully automated analyzers, which are based on the principle of photometry. Photometry is the measurement of light absorbed in the ultraviolet (UV) to visible (VIS) to infrared (IR) range. This measurement is used to determine the amount of an analyte in a solution or liquid. Photometers utilize a specific light source and detectors that convert light passed through a sample solution into a proportional electrical signal. These detectors may be photodiodes, photoresistors, or photomultipliers. Photometry uses Beer–Lambert’s law to calculate coefficients obtained from the transmittance measurement. A correlation between absorbance and analyte concentration is then established by a test-specific calibration function to achieve highly accurate measurements.[24]

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Interfering Factors

Hemolysis, icterus, and lipemia are the most common specimen integrity issues that can interfere with laboratory tests and may lead to erroneous results and interpretations and, ultimately, to inappropriate medical decisions. Oxygenated and deoxygenated hemoglobin have slightly different absorbance spectra but show maximal absorbance around 415 nm, with significant absorbance between 320 and 450 nm and 540 and 580 nm. Colorimetric assays that use absorbance measurements in one or more of these ranges are, therefore, susceptible to interference. Examples include iron, lipase, albumin, and g-glutamyl transferase.

Alkaline phosphatase assays are susceptible to negative interference because alkali denaturation of hemoglobin may cause a negative offset in absorbance readings. Icterus exerts effects on chemistry tests primarily through spectrophotometric and chemical interferences. Bilirubin absorbs light between 400 and 540 nm, with a peak around 460 nm. Colorimetric assays taking primary or secondary absorbance measurements at these wavelengths may be affected. The unconjugated and conjugated forms of bilirubin may exert different effects on certain assays. Conjugated bilirubin has been found to cause a greater degree of interference with most assays.

Lipemia causes light scattering, differential partitioning of analyte between the polar and aqueous phases of the sample, and interaction of the lipoprotein particles with assay reagents may all cause interference in results. Lipaemia causes light scattering across the visual spectrum (300 to 700 nm). Colorimetric assays taking absorbance readings at the shorter wavelengths of the visual spectrum are, therefore, most susceptible to interference. As a result, assays that utilize changes in NAD(P)H concentration, measured around 340 nm, are susceptible to lipaemia interference. ALT levels can increase due to certain drugs, which should be avoided before testing.

Drug hepatotoxicity can be nonidiosyncratic (predictable) or idiosyncratic (unpredictable). Also, drug-associated hepatotoxicity can classify as immune-mediated and non-immune-mediated. The incidence of drug-induced liver injury is 19 cases per 100,000 persons. The most common drug causing drug-induced liver injury is amoxicillin/clavulanate.[25][26][27] Diurnal variations in ALT have been observed in both healthy individuals and those with cirrhosis. Up to 45% variation has been seen, with higher values observed in the afternoon.

Other factors which can affect ALT include body mass index (40 to 50% higher with high body mass index) and exercise (20% lower in those who exercise).[28] Metronidazole may interfere with ALT methods because of its relatively high concentration and absorbance near 340 nm.[29]  Following food ingestion, increases of up to 30 U/L may be seen. In patients with blood groups B and O, these increases can persist for up to 12 hours, attributable to the intestinal isoenzyme. Smoking causes elevated levels of PLALP, which return to the normal range after 1 to 2 months of smoking cessation. During growth, due to increased osteoblastic activity, elevated levels of ALP are seen in children and adolescents. The normal reference range levels also increase with age in females. An unexplained high serum ALP result should always be confirmed with a repeat fasting sample. Increases up to two- or three-fold are normal in the third trimester of pregnancy due to the presence of the placental isoenzyme.

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Results, Reporting, and Critical Findings

The results of liver function tests should correlate with the initial findings in a complete patient history and physical examination. A thorough review should include important questions regarding the patient's age, past medical history (diabetes, obesity, hyperlipidemia, inflammatory bowel disease, celiac sprue, thyroid disorders, autoimmune hepatitis, acquired muscle disorders, alcohol use disorder, medication use, toxin exposure, and family history of genetic liver conditions (Wilson disease, alpha-1-antitrypsin deficiency, hereditary hemochromatosis).[30]

A review of systems should also include signs and symptoms of chronic liver disease such as jaundice, ascites, peripheral edema, hepatosplenomegaly, gynecomastia, testicular hypotrophy, muscle wasting, encephalopathy, pruritus, and gastrointestinal bleeding. Other tests that help determine the cause of elevated transaminase levels found on a hepatitis panel include fasting lipid levels, hemoglobin A1C level, fasting glucose, complete blood count with platelets, a complete metabolic panel, iron studies, hepatitis C antibody, and hepatitis B surface antigen testing.

Reference ranges for LFTs tend to vary depending on the laboratory. Further, normal reference ranges vary between males and females and may be higher for those with a higher body mass index.[24] A patient's blood test values should be interpreted based on the reference value of the laboratory in which the test is done. It is recommended that each laboratory establish its own reference interval based on its methodology.

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Clinical Significance

The levels of LFTs can point to the differentials. Many disease processes have very distinct abnormalities in the liver enzymes. Further investigation is warranted if repeated tests confirm‎ abnormality.

Alcohol

In patients with alcohol use disorder, AST to ALT ratio is generally at least 2:1, showing a high level of AST activity in alcoholic liver disease.[31] Elevated GGT, along with AST, also suggests alcohol abuse. GGT should not be used alone since it is not very specific for alcohol.[32]

Medications

Several medications are known to cause liver damage. Many of these are commonly used in daily practice, including but not limited to NSAIDs, antibiotics, statins, anti-seizure drugs, and drugs for tuberculosis treatment. Acute hepatocellular injury can be seen secondary to several drugs, including but not limited to acetaminophen, allopurinol, NSAIDs, alcohol, anti-tuberculosis medications such as isoniazid, pyrazinamide, rifampin, statins, antifungals such as ketoconazole, antibiotics such as tetracyclines, anti-seizure drugs such as valproic acid and phenytoin, antidepressants such as fluoxetine, antipsychotics such as risperidone and antivirals such as valacyclovir and ritonavir.[25]

Acute cholestasis can be seen secondary to drugs, including anabolic steroids, NSAIDs, tricyclic antidepressants, alcohol, antibiotics such as azithromycin, amoxicillin, nafcillin, rifampin, and trimethoprim-sulfamethoxazole. Long-term use of these agents can also lead to chronic hepatocellular and/or cholestatic liver damage.[26] Methotrexate, the commonly used medication for rheumatoid arthritis and other inflammatory arthritis, can cause a mild transient elevation in LFTs and can also cause permanent liver damage in liver fibrosis and cirrhosis, especially with higher cumulative doses. Liver fibrosis can also be seen as secondary to chronic alcohol intake or methyldopa. Ergot alkaloids can result in ischemic necrosis. Oral contraceptives can result in hepatic venous outflow obstruction (Budd-Chiari syndrome).[33] Herbal medications can also cause an elevation in LFTs.[34]

Viral Hepatitis

Viral illnesses are a common cause of hepatitis and elevation in LFTs. Viral hepatitis B, C, and D can cause chronic hepatitis, while hepatitis A and E cause acute viral hepatitis.[35] Several other viruses, including HIV, Epstein-Barr (EBV), and Cytomegalovirus (CMV), can also cause hepatitis.[36]

Autoimmune Hepatitis

Autoimmune hepatitis is a chronic disease characterized by continuing hepatocellular inflammation, necrosis, and a tendency to progress to cirrhosis. It is more common in young women than men, with a 4:1 ratio. The patient usually presents with high LFTs without apparent cause.[37] These patients can have positive autoantibodies, including antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney microsomal antibodies, and antibodies to the liver antigen.[38]

Hepatic Steatosis and Nonalcoholic Steatohepatitis

Fatty liver disease, aka nonalcoholic steatohepatitis, has recently gained more attention because of its ability to cause chronic hepatic disease and hepatocellular carcinoma (HCC). The typical patient with this disease is overweight, has type II diabetes, or has dyslipidemia and no evidence of clinically significant alcohol use.[39] The AST and ALT are usually both elevated with a ratio of 1:1, with other liver function tests being normal.[40]

Hemochromatosis

Hemochromatosis is abnormal iron accumulation in parenchymal organs, leading to organ toxicity. It is the most common autosomal recessive genetic disorder and the most common cause of severe iron overload. Clinical manifestations include diabetes, liver disease, and cutaneous hyperpigmentation.[41] A raised serum ferritin level usually raises concerns for possible hemochromatosis, but a transferrin saturation greater than 45% is more reliable. HFE mutations (C282Y, H63D) are pivotal for diagnosing hereditary hemochromatosis. Secondary hemochromatosis can also be seen due to increased iron intake.[42]

Wilson Disease

Wilson disease, a rare autosomal-recessive inherited disorder of copper metabolism, is characterized by excess copper deposition in the liver, brain, and other tissues. It is fatal if not recognized and treated early. A low serum ceruloplasmin level is seen in the majority (up to 85%) of the cases.[43] Kayser-Fleischer rings can be a clinical clue but are not always present. The 24-hour urinary copper excretion test is usually abnormal, with more than 100 micrograms of copper excretion in the urine indicating Wilson's disease. A liver biopsy remains the confirm‎atory test.[44]

Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is a relatively common yet often undiagnosed genetic condition.[45]Those with AATD are also predisposed to obstructive pulmonary disease and liver disease (e.g., cirrhosis and hepatocellular carcinoma in children and adults). AATD is one of the most common inherited disorders among Caucasians. Its primary manifestation is early-onset panacinar emphysema.[46]

Celiac Disease

Celiac disease is a common gluten sensitivity disorder associated with modest elevations of liver transaminases; screening should be considered in patients with persistently elevated liver enzymes and consists of tissue transglutaminase IgA and serum IgA level or tissue transglutaminase IgA and anti-deamidated gliadin peptide IgG.[47][48]

Thyroid Disorders

Both hypothyroidism and hyperthyroidism have been associated with abnormal liver enzymes, including both hepatocellular and cholestatic patterns of injury, particularly in more severe cases of myxedema and/or thyrotoxicosis. Screening should be considered in patients with a compatible medical history and consist initially of thyroid stimulating hormone and selective testing of free T4 and free/total T3.[49]

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Quality Control and Lab Safety

For non-waived tests, laboratory regulations require, at the minimum, analysis of at least two levels of control materials once every 24 hours. Laboratories can assay QC samples more frequently if deemed necessary to ensure accurate results. Quality control samples should be assayed after calibration or maintenance of an analyzer to verify the correct method performance. To minimize QC when performing tests for which manufacturers’ recommendations are less than those required by the regulatory agency (such as once per month), the labs can develop an individualized quality control plan (IQCP) that involves performing a risk assessment of potential sources of error in all phases of testing and putting in place a QC plan to reduce the likelihood of errors.[23] Westgard multi-rules are used to eval‎uate the quality control runs. In case of any violation of a rule, proper corrective and preventive action should be taken before patient testing is performed.

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Enhancing Healthcare Team Outcomes

Liver function tests are one of the most commonly ordered laboratory tests. Mild isolated elevations in LFTs can be seen as normal fluctuations and shall not trigger expensive and extensive workups. However, clinicians shall be aware of various conditions that can lead to an elevation in LFTs. Thorough history taking and physical examination can provide clues to the differential diagnosis.

Drug and medication history are of utmost importance. The nursing team shall help with medication reconciliation. Pharmacists can also assist in identifying potentially hepatotoxic agents. Referral to specialists such as hepatologists may sometimes be indicated. An interprofessional team approach can help identify the underlying etiology with appropriate management.[50] This interprofessional team paradigm for patient care, employing good record keeping and open communication lines between different healthcare disciplines, will result in improved patient care. [Level 5]

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Review Questions

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