Elevated Liver Enzymes and Weight Loss

9/13/2006

Nick Siebers, M.D.

“My wife made me come in”

• 50 y/o man returns to our clinic after a 13 year absence.

• CC: “My wife made me come in”

• But… wants to discuss recent labs done for a life insurance physical.

“Life insurance labs”

• AST was elevated at 36 with the normal range for the lab being up to 33.

• ALT was 55 with normal being up to 45.

• Alkaline phosphatase, bilirubin, GGT, total protein and albumin were all normal.

• Hepatitis C antibody was negative.

• Cholesterol panel was normal, HIV was negative, normal urinalysis.

HPI

• Feeling well.

• No abdominal pain, nausea, emesis, jaundice or pruritits, fever, chills or night sweats.

• Does acknowledge a 20-30 pound unintentional weight loss over last 18 months, although this has been stable over last 4 months.

Past Medical History

• Colon cancer in 1993 – s/p hemicolectomy and 5FU x 1 year – at GHC

• Liver imaging several lesions “probable hemangiomas” on ultrasound

• Serial CT scans “Minimal change, maybe slightly larger” - last in 1996

• Pt told “No need for further follow-up” of liver. Colonoscopy negative 2 years ago.

• No other history liver disease

PMHx Cont’d

• Arthritis/low back pain

• Multiple lipomas removed superficially

• Leukocytopenia, resolves with exercise

• H/o blood transfusion

• Ankle fracture

• Allergic rhinitis

Family and Social History

• Father - CAD s/p CABG at age 63• Mother - Breast cancer survivor, thyroid

disease• Aunt and grandfather with colon cancer• Works as an auto mechanic• Drinks about 12 drinks per week, 2 per

day and up to 4 each weekend day• Never smoker, no other drugs, no STD

concerns

ROS

• Weight loss as above• Occasional fatigue• Rare GERD symptoms in past, better recently• Hemorrhoids and occasional rectal bleeding,

including over the preceding few weeks.• Slight chronic cough, rarely productive• Some mild anxiety and insomnia, relatively new,

no depressive symptoms

Exam

• Temp 97.0, Pulse 88 and regular, BMI 21• No jaundice or icterus, no oral lesions• No thyromegaly noted• Heart, lungs normal• Abdomen soft non-tender; liver edge palpable 2-

3 cm below ribs with inspiration, smooth and non-tender; no splenomegaly

• Rectal brown stool, guaiac (+), palpable internal hemorrhoid.

What do I do about these abnormal liver enzymes?

Does “the evidence” help us at all?

Is it a real problem?

What diagnoses to consider?

• Table 282–1. Liver DiseasesInherited hyperbilirubinemia:

– Gilbert's syndrome – Crigler-Najjar syndrome types I and II – Dubin-Johnson syndrome – Rotor syndrome

• Viral hepatitis: – Hepatitis A – Hepatitis B – Hepatitis C – Hepatitis D – Hepatitis E – Others (mononucleosis, herpes, adenovirus hepatitis) 

Cryptogenic hepatitisImmune and autoimmune liver diseases:

Primary biliary cirrhosis Autoimmune hepatitis Sclerosing cholangitis 

Overlap syndromes Graft-vs-host disease Allograft rejection

•  Genetic liver diseases  • Alpha-1-Antitrypsin deficiency • Hemochromatosis•  Wilson's disease•  Benign recurrent intrahepatic cholestasis (BRIC)•  Familial intrahepatic cholestasis (FIC), types I–III•  Others (galactosemia, tyrosinemia, cystic fibrosis, Newman-Pick

disease, Gaucher's disease)• Alcoholic liver disease•  Acute fatty liver•  Acute alcoholic hepatitis•  Laennec's cirrhosis• Nonalcoholic fatty liver•  Steatosis•  Steatohepatitis• Acute fatty liver of pregnancy• Liver involvement in systemic diseases•  Sarcoidosis•  Amyloidosis•  Glycogen storage diseases•  Celiac disease•  Tuberculosis•  Myobacterium avium intracellulare

• Cholestatic syndromes•  Benign postoperative cholestasis•  Jaundice of sepsis•  Total parenteral nutrition (TPN)–induced jaundice•  Cholestasis of pregnancy•  Cholangitis and cholecystitis•  Extrahepatic biliary obstruction (stone, stricture, cancer)•  Biliary atresia•  Caroli's disease•  Cryptosporidiosis• Drug-induced liver disease•  Hepatocellular patterns (isoniazid, acetaminophen)•  Cholestatic patterns (methyltestosterone)•  Mixed patterns (sulfonamides, phenytoin)•  Micro- and macrovesicular steatosis (methotrexate, fialuridine)• Vascular injury•  Venoocclusive disease•  Budd-Chiari syndrome•  Ischemic hepatitis•  Passive congestion•  Portal vein thrombosis•  Nodular regenerative hyperplasia• Mass lesions•  Hepatocellular carcinoma•  Cholangiocarcinoma•  Adenoma•  Focal nodular hyperplasia•  Metastatic tumors•  Abscess•  CystsFrom Harrison's Internal Medicine Copyright ©2006 The McGraw-Hill

Companies.  All rights reserved.

National Health and Nutrition Examination Survey (NHANES)

1999-2002

• Population survey w/ 6,823 participants

• Abnormal ALT in 8.9% of respondents

• Abnormal AST in 4.3%

• Either abnormal in 9.8%

NHANES 1999-2002

• When “history of excessive alcohol consumption” and “Hep C antibody positive” excluded :

• ALT abnormal 7.3%• AST abnormal 3.6%• Either 8.1%• Increased compared with NHANES 1988-

1994 but possibly from differences in specimen handling

NHANES 1988-1994

• 7.9% with elevated ALT or AST

• 31% of these were explained by alcohol consumption, Hep B or C or high transferrin saturation.

• 69% were not!

“Unexplained” Liver Test Elevations

• In NHANES 1988-1994 and 1999-2002, unexplained ALT and AST elevation correlated with:

• BMI and waist circumference• Serum Triglycerides• Fasting insulin• Low HDL• Suggests Fatty Liver Disease as contributing,

although other causes are likely included.

Does it represent disease?

• In 1993, Kundrotas et al. surveyed 19,877 Air Force recruits

• 99 with ALT >2.25 SD above normal (0.5%)• Cause found in only 12 (0.06% of population) –

fatty liver disease not evaluated• Recommended serial ALT testing before further

work-up, frequency and repetitions “not clear”• Later recommendations suggest work up if

chronically elevated for 6 months.

Hultcranz et al. – 1986

• 149 Scandanavian blood donors with elevated ALT, who all had a biopsy:

• 64% with fatty liver

• 20% with chronic active or persistent hepatitis

• 6% with cirrhosis

• Real disease is possible!

Estimates of disease prevalence

• Estimates of cause of elevated ALT/AST vary widely by population studied

Two studies of 249 blood donors:• Alcoholic liver disease 11-48%• Fatty liver 22-56%• Hepatitis C 17-20%• Alpha-1-antitrypsin deficiency 0-4%• Other established dx 4-8%• No Dx 2-9%

Up To Date Recommendations

• “Approach to the patient with abnormal liver function tests” - Daniel S. Pratt author

• 4 step approach to chronically abnormal aminotransferases

• 1) Check for common liver diseases

• 2) Check for non-hepatic causes

• 3) Check less common liver diseases

• 4) Biopsy… or observe

1) Common Liver Diseases

• Medications, herbal therapies, recreational substances

• Alcohol abuse

• Hepatitis B and C serology

• Screen for hemochromatosis

• Evaluate for fatty liver - ultrasound

2) Non-Hepatic sources

• Muscle disorders

• Thyroid disease, hypo- or hyperthyroidism

• Celiac disease

• Adrenal Insufficiency

3) Less Common liver disease

• Autoimmune hepatitis

• Wilson’s disease (if less than 40 y/o)

• Alpha-1-antitrypsin deficiency

• Other diagnoses

• Step 4) – if less than twice upper limit can observe, otherwise biopsy

Labs – 2 weeks off alcohol

• AST 28 (0-50) ALT 66 (0-65)

• Alk Phos 134 (35-130)

• Total bili 0.6 GGT 23

• Iron 138 TIBC 313

• Iron Saturation 44%

• Hepatitis A and B serologies (-)

• CEA < 0.7 undetectable

CT Abdomen and Pelvis

• 1. Three discrete low-attenuation lesions within the posterior segment of the right hepatic lobe. The imaging features are highly suggestive of cavernous hemangioma. Given prior description of similar-appearing lesions from 10 years ago, hemangiomas are even more likely.

• 2. Postsurgical changes of right hemicolectomy. • 3. No evidence to suggest metastatic disease.

Thyroid tests?

• TSH <0.06 - undetectable• Free T4 = 3.5 (0.7-1.8)• Repeat testing was the same. He’s hyperthryroid!• Thyroid uptake and scan findings: The I-131 uptake in 24

hours was normal at 18%. Thyroid scan reveals homogeneous distribution of radioactivity within the thyroid gland with no evidence for salivary gland uptake. IMPRESSION: Data consistent with Graves' disease. However the 24-hour radioiodine uptake is 18%, and not in the range of Graves' disease, because of the contrast material that he received on June 6, 2006 for CT of the abdomen.

Thyroid disease and liver disease

• Long documented associations, going back to 1874 “Exophthalmic goitre; heart disease; jaundice; death.” Lancet by Habershon, SO.

• Liver disease can cause alteration in thyroid function.

• Thyroid disease can cause abnormal liver tests; even severe elevations, jaundice and prolonged PT.

• Case reports exist of chronic active hepatitis that resolved with treatment of hyperthyroidism alone.

Hyperthyroidism and liver tests

Test % with abnormality

AST 27%

ALT 37%

Alk Phos 64%

GGT 17%

Bilirubin 5%

ANY 76%

Hyperthyroidism and liver tests

• Mechanism unclear

• Abnormalities seen on biopsy of hyperthyroidism, but not correlated with lever test abnormalities - 1967

• Couldn’t find more recent literature, and specialists in GI and Endocrine were not able to enlighten me.

Prognosis of abnormal liver tests

• Many normalize with treatment of thyroid disease

• Some transient elevation of ALT and especially Alk Phos with PTU treatment – usually no serious sequella, can continue therapy unless overt hepatitis develops.

Mr. N

• Seen by endocrine! And his thyroid wasn’t felt to be enlarged.

• Being treated for Grave’s Disease with PTU, plan treatment for one year then withdraw and monitor.

• ALT has normalized, alk phos up slightly• He feels great and is VERY happy with these

results – decreased tremor and anxiety, better sleep, weight going up, no cancer.

• Per Dr. Nolten – hyperthyroidism is likely the cause of his abnormal liver tests.

Conclusions

• Work up common liver diseases first, with focus as per history

• If abnormal liver tests – think of the thyroid!

• It is possible to get a patient in to see endocrine, although it takes some doing.

References• Pratt, DS. Approach to the patient with abnormal liver function tests. Up To Date

2006.• Katkov, WN, et al. Elevated serum alanine aminotransferase levels in blood donors:

the contiburion of hepatitis C virus. Annals ot Internal Medicine 1991; 115:882.• Hulcrantz, R, et al. Liver investigations in 149 asymptomatic patients with moderately

elevated activities of serum aminotransferases. Scandanavian Journal of Gastroenterology 1986; 21:109.

• Ioannou, GN, et al. the Prevalence and Predictors of Elevated Serum Aminotransferase Activity in the United States in 1999-2002. American Journal of Gastroenterology 2006; 101:76-82.

• Huang, M, et al. Sequential Liver and Bone Biochemical Changes in Hyperthyroidism: Prospective Controlled Follow-up Study. American Journal of Gastroenterology 1994; 89:1071-1076

• Fong, T, Et al. Hyperthyroidism and Hepatic Dysfunction: A case Series Analysis. Journal of Clinical Gastroenterology 1992; 14:240-244.

• Leeuwenburgh, I, et al. Recovery of Chronic Hepatitis by Treatment of Concomitant Hyperthyroidism. European Journal of Gastroenterology and Hepatology 2001: 13:1389-1392.

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