Liver Disease

Thomas C Sodeman MD FACPAssociate Professor of Medicine

Chief, Division of HepatologyUniversity of Toledo

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Liver Disease

• Approach to abnormal labs– AST– ALT– Alkaline phosphatase– Bilirubin

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Liver Disease

• Laboratory patterns– Hepatitis

• AST/ALT//Alkaline phosphatase

– Cholestatic• Bilirubin/alkaline phosphatase//AST/ALT

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Liver Disease

• Laboratory patterns– Hepatitis

• AST/ALT < 1000 viral

– Hepatitis• AST/ALT > 5000 fulminant hepatitis

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You are seeing a 24 year old male to establish care. He states he has had no medical issues, but has noticed his eyes will turn yellow when he has a cold. He is concerned that he may develop cirrhosis like his father, who drank heavily. He is on no medications, and his examination is normal. His total bilirubin is 2.3 mg/dL, direct bilirubin 0.2 mg/dL. Your next evaluations should be:

a. Reassurance

b. CT scan of the liver

c. Hepatitis serologies

d. Liver biopsy

e. HFE gene study

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Liver Disease

• Hyperbilirubinemia– Unconjugated – increased production

• Hemolysis

– Conjugated - dysfunction– Gilbert’s syndrome– Elevated total bilirubin – unconjugated– Fasting / illness

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You are asked to see a 67 year old male found at home and hospitalized. He has a past history of hypertension and dementia. His diet recently had consisted of only prune juice and celery. He is disheveled looking, emaciated, and has multiple bruises on his upper and lower extremities. His labs show an albumen of 1.3, normal transaminases, a microcytic anemia, and an INR of 2.5. He takes no medications at home. Your next step to evaluate his elevated INR would be:

a. Hepatitis serologies

b. Ceruloplasmin

c. Ultrasound of the liver

d. Vitamin K supplementation

e. Liver biopsy

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Liver Disease

• Measures of synthetic function– Short term

• PT/INR

– Longer term• Albumen

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Liver Disease

• Measures of synthetic function– INR elevation due to malabsorption vs.

dysfunction– Malabsorption responds to vitamin K

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Liver Disease

• Other evaluations– Radiologic– Pathologic– Functional

• HIDA

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Liver Disease

• Radiologic– Ultrasound – masses, flow, fat– CT – masses, fat– MR – masses, fat– PET – malignancy– ERCP – ‘plumbing’

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Liver Disease

• Pathologic– Diagnosis – used when labs / imaging unclear– Staging – degree of fibrosis – important for

treatment decisions and prognosis

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Your patient, a 25 year old female, just returned from a vacation in Mexico a month ago. Recently she has been feeling fatigued, and has had modest right upper quadrant discomfort. Yesterday she noticed that her eyes were yellow. Past medical history is significant for asthma, current medication is an inhaler. Physical exam reveals scleral icterus, and a slightly enlarged liver. Laboratories show an INR of 1.0, AST 450 U/L, ALT 435 U/L, and bilirubin of 3.2 mg/dL. Your next evaluation would be:

a. Intravenous immunoglobulinb. Referral for liver transplantationc. Referral for alcohol treatmentd. Lamivudine 100mg po QDe. HAV IgM

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Liver Disease

• Hepatitis A– Incubation 2-6 weeks– Fecal oral– IgM anti HAV– No treatment– No chronic condition– Ig for contacts– Vaccine for travelers

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Your patient comes in with jaundice. He is a 30 year old male with a history of intravenous drug abuse. He has not recently traveled, and drinks 2 to 3 beers a day. On examination he has scleral icterus and jaundice, no asterixis, no ascites or edema, and no stigmata of chronic liver disease. Past screening has been negative for viral hepatitis, and past medical history is unremarkable. Labs show as AST of 1000 U/L, ALT 1200 U/L, alkaline phosphatase of 150 U/L, total bilirubin of 3.0 mg/DL, and an INR of 1.2. Your next step should be:

a. Referral for liver transplantationb. CT scan of the liverc. Hepatitis serologiesd. Liver biopsye. Lamivudine 100 mg PO QD

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Liver Disease

• Hepatitis B– Incubation 4 – 24 weeks– Parenteral– HBsAg, HBsAb– HB core Ab– HB e Ag, Ab– HBV DNA

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Liver DiseaseHBsAg Anti HBs IgM anti

HBcIgG anti

HBcHBeAg Anti HBe DNA

+ - + - + - + Acute

- + - + - -/+ - Immune

- + - - - - - Vaccinated

+ - - + - + <105/mL Carrier

+ - - + + - >105/mL Chronic replicating

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Your patient comes for evaluation of her chronic hepatitis. She is a 53 year old nurse who contracted hepatitis B via a needle stick. She does not drink alcohol, and has well controlled hypertension. Examination is normal, labs show AST and ALT twice normal, and HBV DNA PCR shows 1,300,000 copies / mL. Liver biopsy showed minimal fibrosis and moderate portal and parenchymal inflammation. Your next step would be:

a. Reassurance

b. CT scan of the liver

c. Referral for liver transplantation

d. Tenofovir

e. Repeat liver biopsy in one year

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Liver Disease

• Hepatitis B– Fulminant

• Initial or reactivation

– Chronic• Cirrhosis• Hepatocellular carcinoma

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Liver Disease

• Hepatitis B– Treatment

• Evidence of inflammation (biopsy, enzymes)• Elevated DNA (<10000 copies / mL)

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Liver Disease

• Hepatitis B– Treatment

• Interferon – not in cirrhosis• Lamivudine - resistance• Adefovir• Entecavir

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Your patient presents for further evaluation of hepatitis C found at blood donation. He is a 54 year old male in otherwise good health, and his route of acquisition is a transfusion at age 10. His examination is normal, labs show AST and ALT 1.5 times normal, genotype of 1a, and a viral load of 2,300,000 IU/mL. Testing at donation showed a viral level of 1,400,000 IU/mL 4 months ago. Your next step is:

a. Pegylated interferon and ribavirin

b. CT scan of the liver

c. reassurance

d. Liver biopsy

e. HFE gene study

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Liver Disease

• Hepatitis C– Incubation 2-10 weeks– Parenteral– Pre late 1980’s – transfusion / IVDU– Now - IVDU

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Liver Disease

• Hepatitis C– Diagnosis

• Initial – anti HCV• Confirmation – RNA PCR – not RIBA• Additional – genotype, viral load• Biopsy – long duration, duration unknown,

confounding factors (alcohol)

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Liver Disease

• Hepatitis C– Treatment

• Stage ≥2• Not viral load

– Interferon / ribavirin• Length depends upon genotype

– 1 – 48 weeks– 2,3 – 24 weeks

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Liver Disease

• Hepatitis C– Treatment

• Side effects– Depression – (suicide)– Fatigue– Aches– Cytopenias (RBC / WBC / plt)– Thyroid– Hair loss– Weight loss

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Liver Disease

• Hepatitis C– Treatment

• Reasons to stop treatment– Suicidal ideation– No response at 3 months (2 log drop viral load)– Intolerance of side effects– Not cytopenias unless severe

» First try growth agents» PLT < 10,000» ANC <750» Severe anemia

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Liver Disease

• Hepatitis D– Incubation 4-24 weeks– Parenteral - IVDU– Coinfection– Superinfection– Treat HBV

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Liver Disease

• Hepatitis E– Incubation 2 – 9 weeks– Parenteral– Rare in US– Similar to HAV– 20% mortality in pregnancy

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Liver Disease

• CMV

• EBV

• HZV - pregnancy

• Adenovirus

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Your patient presents for evaluation of fatigue, She is a 65 year old retired teacher with a past medical history of hypothyroidism and hypertension, under control. Examination reveals slight hepatomegaly and 1+ pitting edema at the ankles. Laboratories show AST and ALT 1.5 times normal, normal bilirubin and alkaline phosphatase, and a normal CBC. Your next step is:

a. Reassurance

b. CT scan of the liver

c. Hepatitis serologies

d. ANA and serum protein electrophoresis

e. Alcohol counseling

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Liver Disease

• Autoimmune hepatitis– Distribution 3:1 F:M– Peaks 10-20 years, 50 years– Presentation

• Chronic• Fulminant

– 1/3 with another autoimmune disorder

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Liver Disease

• Autoimmune hepatitis– Fatigue– Jaundice– Anorexia– Myalgia

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Liver Disease

• Autoimmune hepatitis– Ast Alt ≈ 500 (>1000)– ANA >1:80– ASMA > 1:80– LKM1 >1:80– Gamma globulin > 1.5x normal

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Liver Disease

• Autoimmune hepatitis– Biopsy– Interface hepatitis– Plasma cells

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Liver Disease

• Autoimmune hepatitis– Treatment

• Prednisone / imuran– 80% remission– 2 years– Relapse in 50%– Retreat relapsers

• 90% mortality untreated

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Your patient, a 58 year old woman, presents with one month of pruritus. She has no significant past medical or exposure history, no recent travel or new pets. Examination shows xanthomas and excoriations, and otherwise is normal. Labs show AST and ALT twice normal, and alkaline phosphatase of 450 U/L, total bilirubin of 1.2 mg/dL. The your next step should be:

a. Reassurance

b. CT scan of the liver

c. Hepatitis serologies

d. Liver biopsy

e. Anti mitochondrial antibody

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Liver Disease

• Primary biliary cirrhosis– Small bile duct– 9:1 M:F– Age 40-60– Elevated alkaline phosphatase– Pruritus / fatigue – AMA > 1:40– Ursodeoxycholic acid 12 -15 mg/kg– Osteoporosis

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Your patient, a 24 year old male with a 10 year history of ulcerative colitis, presents for a routine evaluation. His colitis has been under control with Asacol, and he has no other significant medical issues. Examination is unremarkable. Laboratories show AST and ALT twice normal, Alkaline phosphatase 450, total bilirubin of 1.4 mg/dL, and a normal CBC. Your next step is:

a. Reassurance

b. CT scan of the liver

c. Hepatitis serologies

d. ERCP

e. Liver biopsy

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Liver Disease

• Primary sclerosing cholangitis– Medium and large duct disease– 80% associated with ulcerative colitis– Increased alkaline phosphatase– Dominant strictures– Cholangiocarcinoma / colon ca– Osteoporosis– No effective treatment

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Your patient presents for routine follow up. He is a 53 year old lawyer with a past medical history of hypertension, elevated cholesterol and type 2 diabetes. He is on therapy for all three diseases. Examination is normal except for obesity. Labs show a normal AST, ALT of 60 U/L, normal alkaline phosphatase and bilirubin. Previous labs have been normal. Your next step should be:

a. Reassurance

b. CT scan of the liver

c. Hepatitis serologies

d. Liver biopsy

e. Repeat labs in 3 months

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Liver Disease

• NASH– Fatty liver – cirrhosis– Obesity– DM– Hyperlipidemia– TPN– ALT>AST <200– Diagnosis of exclusion

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Liver Disease

• NASH– Treatment

• Weight loss• Control of diabetes / lipids• Gastric bypass• PPAR- agents

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Liver Disease

• Alcoholic liver disease– Alcoholic liver disease

• 80 g / d men• 40 g / d women• AST 2x ALT <300

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Liver Disease

• Alcoholic liver disease– Alcoholic hepatitis

• Elevated AST>ALT bilirubin INR WBC• Discriminant function >35

• 4.6[Pt-Ptcontrol] + bil (mg/dL)

• Neutrophils on biopsy• Treatment

– Prednisone / pentoxyphylline / TNF agents

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You are seeing a new patient, a 35 year old male. He complains of some fatigue, but otherwise is in good health. Examination is normal. His family history includes cirrhosis in an uncle and CAD. Labs show normal liver enzymes, a ferritin of 750 mg/L, and iron saturation of 88%. Your next step is:

a. Reassurance

b. CT scan of the liver

c. HFE gene study

d. Hepatitis serologies

e. Liver biopsy with quantitative iron level

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Liver Disease

• Hereditary Hemochromatosis– Most common inherited disorder in Europeans– C282Y H63D– Autosomal recessive– Ferritin elevation

• 400

– Iron saturation• 50%

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Liver Disease

• Hereditary Hemochromatosis– Diabetes– Cardiomyopathy– Arthritis PIP/DIP

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Liver Disease

• Hereditary Hemochromatosis– Ferritin > 1000 / elevated AST – biopsy– No role for iron index

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Your patient , a 35 year old male with hereditary hemochromatosis (C282Y/C282Y) presents asking about therapeutic options. His labs showed AST and ALT twice normal, ferritin of 1300 mg/L, iron saturation of 92%. Liver biopsy showed minimally increased fibrosis. Your next step is:

a. Reassurance

b. Chelation with desferroximine

c. Weekly therapeutic phlebotomy

d. Low iron diet and observation

e. Penicillamine therapy

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Liver Disease

• Hereditary Hemochromatosis– Phlebotomy

• Initially weekly

– Ferritin<50• Q three months

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You are seeing a 22 year old female in the hospital for elevated liver enzymes. She was hospitalized for acute psychosis a week earlier. On examination she has choreaform movements of her hands, and otherwise examination is normal. Labs show AST and ALT twice normal, an alkaline phosphatase of 50 U/L, and is otherwise normal. Your next step is:

a. No further testing

b. Serum ceruloplasmin

c. Spot urine copper

d. Liver biopsy

e. Hepatitis serologies

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Liver Disease

• Wilson’s disease– Age 15-40

• Acute – fulminant failure– Hemolytic anemia

• Chronic – cirrhosis

• Ceruloplasmin <20 mg/dL

• 24 hour urine copper >80 mg/24h (>250)

• Psychiatric symptoms

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Liver Disease

• Wilson’s disease– ATPB7

• Treatment– Penicillamine– Trientine lifetime– Zinc– Transplant – FHF, cirrhosis

• curative

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Liver Disease

• Alpha-1 antitrypsin– Phenotype– ZZ– SS– SZ– MZ– MM– Null / null

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Liver Disease

• Alpha -1 antitrypsin– Variable presentation– Cirrhosis– Emphysema– Neither– HCC

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Liver Disease

• Storage diseases– Amyloid– Glycogen storage– Lipopolysaccharidoses

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Liver Disease

• Liver masses– Benign

• Usually asymptomatic unless very large• Found incidentally

– Malignant• Metastatic / primary• Primary more likely with cirrhosis

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You are seeing your patient in follow up for an abnormal CT. She is 45 and had a CT in the emergency room for nephrolithiasis, which has resolved. She has no significant past medical history, and is on no medications. Repeat CT with contrast shows a 2cm mass with peripheral enhancement in the left lobe, and a 3cm mass in the right, also with the same enhancement. Your next step is:

a. Reassurance

b. CT guided liver biopsy

c. Serum E. histolytica antibodies

d. Referral for surgery

e. Serum alpha fetoprotein

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Liver Disease

• Liver masses– Benign - CT

• Adenoma – OCP / hormones– Irregular enhancement

• Hemangioma – most common– Peripheral enhancement

• Focal nodular hyperplasia– Central scar

• Cysts– Hypodense

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Your patient presents for follow up of an abnormal CT scan. He is a 54 year old with a history of alcoholic cirrhosis, complicated by ascites and modest encephalopathy. CT showed a 3cm mass in the right lobe with arterial enhancement, and nodularity of the liver consistent with cirrhosis. INR is 2.2, bilirubin is 3.1 mg/dL, and ascites was present. Your next step is:

a. Referral for hospice

b. CT guided liver biopsy of the mass

c. Referral for systemic chemotherapy

d. Referral for liver transplantation

e. Referral for surgical removal of mass

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Liver Disease

• Liver masses– Malignant

• Metastatic• Hepatocellular carcinoma

– Arterial phase enhancement– Underlying disease

• Cholangiocarcinoma

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Liver Disease

• Liver masses– Abscesses

• Amoebic– Often not associated with colitis– Metronidazole

• Pyogenic– Diverticulitis– Non-enhancing– Drainage

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Liver Disease

• Drug hepatotoxicity– Acute– Chronic– Idiopathic

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Liver Disease

• Drug hepatotoxicity– Acute– Chronic– Idiopathic

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Liver Disease

• Drug hepatotoxicity– Acute

• Acetaminophen• Isoniazid• Dantrolene• Nitrofurantoin• Sulfonamides• Phenytoin• Disulfiram• Ketoconazole

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Liver Disease

• Drug hepatotoxicity– Chronic

• Nitrofurantoin• Etretinate• Diclofenac• Minocycline• Trazadone

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Liver Disease

• Drug hepatotoxicity– Chronic – Granulomatous – alkaline phosphatase

• Allopurinol• Carbamazepine• Hydralazine• Quinidine

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Liver Disease

• Fulminant failure– Acute liver failure (jaundice, INR)– Encephalopathy– No pre-existing liver disease

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Liver Disease

• Fulminant failure– Acetaminophen

• 24 hour nomogram• Mucomyst

– Viral• HAV, HBV

– Ischemic– Wilson’s

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Liver Disease

• Cirrhosis– Encephalopathy– Ascites– Varices– Hepatorenal syndrome– Hepatocellular carcinoma– Transplant

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Your patient present for follow up She is a 45 year old with a history of cirrhosis secondary to alcohol and hepatitis C. her manifestations have included ascites, treated with furosemide and aldactone, and encephalopathy, treated with lactulose. She denies any forgetfulness as does her husband. Her labs show an ammonia of 120 g/dL, up from 98 g/dL last month. Your next step is:

a. Reassurance

b. Increase lactulose

c. Add oral neomycin

d. Restrict dietary protein

e. Increase diuretics

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Liver Disease

• Encephalopathy– Elevated ammonia– Predisposing factors

• Bleeding• Diet• Constipation• Infection

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Liver Disease

• Encephalopathy– Treatment

• Lactulose - compliance• Neomycin – ototoxicity• Flagyl• Xifaxin• Zinc

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Liver Disease

• Varices– Esophageal– Gastric– Rectal– Screening

• Dx of cirrhosis• Grade 1-2 – repeat 1-2 years• Grade 3-4 – banding / blockers

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You are seeing a patient in the emergency room. He is a 28 year old with a history of excessive alcohol intake for 12 years. He presented with large volume emesis of bright red blood. His hemoglobin is 6.2 g/dL, INR 3.4, platelets 22,000 / L. A central line has been placed, fluid resuscitation has been started, and the gastroenterologist has been called. Your next step is:

a. Placement of a Sengstaken-Blakemore tube

b. Endotracheal intubation

c. Platelet transfusion

d. Fresh frozen plasma

e. Emergent TIPS placement

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Liver Disease

• Varices– Active bleeding– Treatment

• Intubation• Transfusion to Hb 8• Banding• Sclerosis• Sengstaken Blakemore• TIPS• Surgical shunt

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Liver Disease

• Portal hypertensive gastropathy– Iron deficiency anemia– Responds to -blockers

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You are seeing a 46 year old in follow up. She has cirrhosis secondary to autoimmune hepatitis, and has recently developed lower extremity edema and non-tense ascites. Examination is otherwise unremarkable, and labs show a creatinine of 1.0 mg/dL, and an albumen of 2.1 g/dL. She is currently on furosemide 20 mg/day. Your next step is:

a. Change to aldactone 100 mg / day

b. Salt restriction to 500 mg / day

c. Fluid restriction to 1 liter / day

d. Increase furosemide to 40 mg / day and add aldactone 100 mg / day

e. Albumen infusion

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Liver Disease

• Ascites– Decreased albumen – oncotic pressure– Increased portal pressure– Increased splanchnic blood flow– Increased water retention due to activation of

renin / angiotensin / aldosterone axis

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Liver Disease

• Ascites– Initial evaluation

• Hepatic vs cardiac• Tap

– OK if INR up / plt down– SAAG– Cell Count– Culture– ? cytology

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Liver Disease

• Ascites– Treatment– Aldactone 100 mg/day– Lasix 40 mg / day– Max 400 / 160– Sodium / water restrictions

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Liver Disease

• Ascites– Tap – risk of HRS – replace albumen 8g/L

– Indications for repeat taps• ? Infection• Diuretic resistance

– TIPS• Diuretic resistance

– Denver shunt

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Liver Disease

• Spontaneous bacterial peritonitis– Often asymptomatic– Monobacterial– Ascitic fluid cell count / culture

• > 250 PMN

– Inpatient – cefotaxime– Outpatient - quinolone– Prophylaxis – after one episode

• Weekly quinolone

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Liver Disease

• Hepatorenal syndrome– Renal vasoconstriction– Cr > 1.5 mg/dL or CrCl <40 mL/min– Urine protein <500 mg/d– No shock– No renal parenchymal disease– No improvement after stopping diuretics /

1.5 L NS challenge

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Liver Disease

• Hepatorenal syndrome– Indication for transplant– TIPS

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Liver Disease

• Hepatocellular carcinoma– Rare in no liver disease– Often asymptomatic

• Pain, weight loss, fever

– Worse risk• Hemochromatosis , α1AT, HBV

– Alpha fetoprotein – Q six months• <100• Trend• >500

– Scans Q six months

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Your patient presents for follow up. She is 54, and has a history of cirrhosis secondary to hepatitis C, which has not been treated yet. She has no encephalopathy or ascites, and other than fatigue feels well. Labs show an INR of 1.1, bilirubin of 1.2 mg/dL, platelets of 98,000 / mL, creatinine of 1.1 mg/dL, and a viral load of 1,300,000 IU/mL. Endoscopy recently shoed no esophageal varices. She is concerned about getting on a transplant list. Your next step is:

a. Reassurance

b. Referral for transplantation

c. Referral for liver biopsy

d. Referral for hospice

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Liver Disease

• Liver transplantation– Indication

• Dysfunction• Hepatocellular carcinoma• Storage / metabolic problems

– MELD score• 5 – normal• 5-15 – below listing• >15 – listable

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Liver Disease

• Liver transplantation– Contraindications

• Active infection• Extrahepatic malignancy• HIV• Severe extrahepatic diseases – CAD, COPD• noncompliance

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Liver Disease

• Liver transplantation– Post transplant issues

• Diabetes• Hypertension• Renal insufficiency• Recurrence of disease

– HCV/PBC/PSC/AIH

• Rejection• Plumbing - anastamoses• Malignancy - skin

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Liver Disease

• Vaccination– HBV

• Health care workers, jail, sewer, military• Children

– HAV• Travel to endemic areas

– Underlying liver disease• Recommended in all