Disorders of the Liver

Definition

• homozygosity for C282Y mutation

• hepcidin deficiency

  • hepcidin is secreted by the liver and regulates iron release from macrophages and duodenal enterocytes by interacting with ferroportin inhibiting iron trasnport

  • HFE, Transferin Receptor 2 (TfR2), and Hemojuvulin regular expression of hepcidin in response to the body's iron needs

    • dysfunction of any of these results in unrestricted flow of iron into the plasma

    • mutations are associated with reduced hepcidin levels

• ferroportin disease

  • mutation in ferroportin gene makes ferroportin unresponsive to inhibitor action of hepcidin on iron transport

  • results in unregulated release of iron into the plasma despite normal hepcidin levels

Signs and Symptoms

• Diabetes mellitus

  • usually improves with iron depleting therapy

• Congestive heart failure

  • usually improves with iron depleting therapy

• Arthropathy

  • less responsive to iron depleting therapy

• Hypogonadism

  • less responsive to iron depleting therapy

• Malaise

• Abnormal skin pigmentation

  • may be improved with iron depleting therapy

Lab Findings

• elevated liver enzymes

• elevated iron saturation

• elevated ferritin

  • Ferritin >1000 is associated with increased risk for advanced fibrosis or cirrhosis

    • warrants liver biopsy

Pathology Findings

• Intrahepatic iron staining

• Fibrosis

Treatment

• Phlebotomy

• Iron chelators if phlebotomy cannot be tolerated

Definition

• associated with ATP7B gene mutation on chromosome 13

  • impacts a copper transport protein, P-type ATPase that mediates excretion of copper into the bile

  • failure to excrete copper leads to deposition in the liver, eyes, and brain

• Diagnosis suggested by...

  • serum ceruloplasmin <20 mg/dL - warrants further work up for Wilson's Disease

    • serum ceruloplasmin <5 mg/L is highly suggestive

  • serum copper levels often decreased due to decrease in circulating ceruloplasmin, the major serum copper binding protein

  • non-ceruloplasmin bound copper elevated, typically >250 mcg/L

  • 24 hr urine copper level > 100 mcg is highly suggestive

    • levels > 40 mcg/24hr warrant additional testing

  • Liver biopsy with hepatic copper content >250 mcg/gram highly suggestive

  • Kayser-Fleischer rings are highly suggestive

    • this finding is seen in only 44-62% of cases of isolated hepatic disease

    • it is almost always present in those with neurologic wilson's disease

Signs and Symptoms

• Acute fulminant hepatitis

  • marked transaminitis

  • evidence of liver failure

  • low alkaline phosphatase

  • Coombs negative hemolytic anemia

    • due to copper-induced lysis of RBCs

• Chronic progressive liver injury leading to cirrhosis

• Psychiatric history

  • due to deposition of copper in the basal ganglia and other structures

  • Parkinsonian movement disorders

  • dysautonomia

  • psychotic disorders

Lab Findings

• elevated AST/ALT

• low alkaline phosphatase

• Diagnosis

  • serum ceruloplasmin <20 mg/dL - warrants further work up for Wilson's Disease

Treatment

• Copper chelation therapy

  • Trientine

  • D-penicillamine

  • zinc

• patients on therapy should have 24-hr urine copper determination every 6 mo

  • Trientine or D-penicillamine - goal urine copper excretion 200-500 mcg/24hr

  • zinc - goal urine copper excretion 75 mcg/24hr

Definition

• rare metabolic disorder

  • affecting 1/12,000-100,000 newborns of European descent

  • significantly more common in French-Canadian lineages

• metabolism of tyrosine leads to production of acetoacetate or fumarate

  • lacking fumaryloacetate hydrolase, a toxic intermediate accumulates

  • leads to elevated serum succinoacetone

Signs and Symptoms

• presents in infants

• hypoglycemia

• jaundice

• failure to thrive

• hepatomegaly

• Fanconi syndrome

  • FTA

  • phosphate wasting

  • aminoaciduria

• may present as rapidly progressive liver disease or progress slowly to cirrhosis

  • elevated risk of HCC

Labs Findings

• elevated serum succinoacetone

• markedly elevated AFP

• aminoaciduria

• renal tubular acidosis

• AST/ALT, AP, and TBili elevation

Treatment

• If he disease is diagnosed early in newborn screening, treat with...

  • diet low in tyrosine and phenylalanine

  • nitisinone - blocks early steps in the tyrosine pathway and prevents formation of toxic metabolites

• liver transplantation for those with severe disease or who are unresponsive to therapy

Risk Factors

• psoriasis

  • associated with NAFLD

  • may be associated with increased risk for fibrosis

Definition

• definition diagnosis requires liver biopsy

• leading cause of death in those with NASH is cardiovascular disease

• affects 2-3% of the US population and is expected to become the leading indication for liver transplant

Lab Findings

• ALT elevation > AST

Pathology Findings

• ballooning hepatocytes

• steatosis

• lobular inflammation

• portal inflammation may sometimes be seen

  • particularly in young patient's with NASH

• Mallory hyaline may be seen but it is not necessary for histologic diagnosis

Treatment

• Vitamin E

  • improves steatosis and inflammation but is not associated with improved fibrosis

• weight loss

  • bariatric surgery is effective and cost-effective for obese patients with NASH, regardless of fibrosis stage in the absence of decompensation

Definition

• a chronic inflammatory disorder of the liver characterized by

  • elevated transaminases

  • positive autoimmune serologies

  • elevated immunoglobulin levels

  • varying degrees of liver damage

• liver biopsy is indicated to assess the degree of active inflammatory disease

  • if inflammation is present, initiate therapy

Signs and Symptoms

• varied presentation

  • asymptomatic disease with abnormal liver enzymes

  • decompensated cirrhosis

  • acute hepatitis with markedly elevated transaminases

  • acute liver failure

• cirrhosis

  • present at diagnosis in ~1/3 of adults and up to 1/2 of children with AIH

Risk Factors

• personal or family history of autoimmune conditions

• female gender (sex ratio 3.6:1)

Lab Findings

• acute presentations often lack autoantibodies with normal gammaglobulin levels

• Type 1 AIH

  • ANA

  • anti-smooth muscle antibodies (ASMA)

  • anti-soluble liver antigen (SLA)

• Type 2 AIH

  • seen more often in children

  • anti-liver-kidney-microsomal (LKM) antibody

  • anti-LC-1 antibody

• Standard screening

  • ANA

  • ASMA

  • anti-LKM

  • pursue other antibodies in equivocal cases

Pathology Findings

• interface hepatitis and plasma cells

• hepatocyte rosettes

Treatment

• corticosteroids (IV solumedrol or prednisone) alone

  • there is some data for budesonide in place of prednisone but this is not as effective in those with cirrhosis or advanced fibrosis

• corticosteroids combined with azathioprine

  • combination regimen allows for lower doses of steroids and lower incidence of side effects

  • same therapeutic efficacy as steroids alone

  • Risk of azathioprine induced pancreatitis

• mycophenolate mofetil and calcineurin inhibitor (ex. cyclosporin)

  • in those who fail to respond or are intolerant of azathioprine

Definition

• genetic variation in ABCC2 gene

  • results in defect in canalicular transport of conjugated bilirubin into the bile duct

• do not develop liver failure and are not at increased risk for HCC

Lab Findings

• normal liver enzymes

• normal serum bile acid levels or mildly increased conjugated bilirubin

Pathology Findings

• liver appears black on gross examination

Lab Findings

• increased conjugated bilirubin

Definition

• caused by deficient lysosomal acid lipase activity

  • results in cholesteryl ester accumulation in the liver, spleen, and macrophages

• leads to liver failure, accelerated atherosclerosis, and premature death

Pathology Findings

• microvesicular steatosis

  • Versus

    • Celiac disease may be associated with MACROvesicular steatosis

    • Drugs that may be associated with microvesicular steatosis

      • aspirin

      • valproate

      • nucleoside reverse transcriptase inhibitors

      • cocaine

      • tetracycline

    • Also seen in acute fatty liver of pregnancy

      • NOT seen in intrahepatic cholestasis of pregnancy

Defintion

• previously known as hepatic veno-occlusive disease

• injury to sinusoidal vascular epithelium leading to

  • fibrinogen deposition

  • vascular congestion

  • eventually hepatocyte necrosis in a centrilobular pattern

• most often seen in patients undergoing hematopoietic stem cell transplant

  • associated with specific myeloablative regimens, particularly with cyclophosphamide or high dose XRT

• also seen after exposure to other toxins

  • Jamaican "bush tea" - beverage containing pyrrolizidine alkaloids

• Seattle criteria for diagnosis

  • serum bilirubin >2 mg/dL

  • hepatomegaly or RUQ pain

  • weight gain >2% of body weight

• Baltimore criteria for diagnosis

  • serum bilirubin >2 mg/dL

  • Two of the following

    • hepatomegaly

    • ascites

    • weiht gain >5% of body weight

Signs and Symptoms

• rapid onset ascites, edema, weight gain

• typically within weeks of HSCT

• tender hepatomegaly

• elevated AST/ALT, bilirubin

• minority develop overt hepatic failure with encephalopathy and coagulopathy

Treatment

• incidence can be reduced by

  • choosing a less toxic myeloablative regimen

  • administering UDCA or low dose heparin in the pre-transplant period

Definition

Risk Factors

• African American women

Lab Findings

• elevated serum angiotensin converting enzyme level

  • not diagnostic of hepatic sarcoid as can be seen in other disorders

• normal or only mildly elevate liver enzymes

• elevated serum alkaline phosphatase

Imaging Findings

• CXR - bilateral hilar adenopathy

• Abdominal ultrasound - enlarged and heterogenous appearing liver

Pathology Findings

• Liver biopsy - multiple small non-caseating granulomas

Treatment

• though corticosteroids are useful in management, not all patients with hepatic sarcoid require treatment

  • in asymptomatic patients it is unclear if steroids prevent liver damage or halt the progression of disease

  • diagnosis of hepatic sarcoid alone does not compel initiation of steroids

Defintion

• hepatic venous outflow derangement

Signs and Symptoms

• new onset ascites

• elevated liver enzymes

Imaging Results

• abdominal ultrasound with doppler

  • hepatic caudate lobe hypertrophy

    • due to separate venous drainage of the caudate into the inferior vena cava

    • allows for sparing of the outflow and compensatory hypertrophy

  • intrahepatic or subcapsular hepatic venous collaterals

    • identified in up to 80% of patients

• CT with contrast

  • early homogeneous central enhancement

  • delayed patchy enhancement of the peripheral liver

  • prolonged retention of contrast in the hepatic periphery

  • inhomogenous portal perfusion

Lab Findings

• Ascitic fluid

  • SAAG characteristically 1.1 or more

  • elevated total protein

Definition

• Prognosis can be estimated using

  • MELD score

  • Maddrey Discriminant Function

    • DF >32 predicts a 20-50 percent 30 day mortality

      • treat with prednisolone

Diagnosis

• Probably Alcoholic hepatitis

  • heavy alcohol use for >5 years

  • active alcohol use until four weeks prior to presentation

  • sudden onset or worsenign jaundice

  • AST/ALT >1.5 with levels <400 IU/L

  • absence of other causes of liver disease

Signs and Symptoms

• onset or sudden worsening of jaundice

  • with or without signs of hepatic dysfunction

• may have stigmata of liver cirrhosis

• may meet SIRS criteria due to significant inflammatory response in the liver

Risk Factors

• history of heavy alcohol use

Lab Findings

• AST/ALT ratio >1.5

• total AST or ALT <400 IU/L

Pathology Findings

• Liver biopsy, not routinely performed but would show...

  • macrovesicular steatosis, ballooning degeneration

  • neutrophilic lobulitis

  • Mallory-Denk bodies

  • pericellular fibrosis

  • These findings can also be seen in NASH, so history is crucial

Treatment

• Abstinence

• Maddrey Discriminant Function >32

  • treat with prednisolone

• Lille score

  • calculate at day seven to assess response to therapy

  • continue therapy for 28 d in initial responders

• Pentoxifylline

  • variable data showing possible benefit

  • not currently recommended

• Infliximab

  • severe infectious complications prevent use

Treatment

• Abstinence

  • baclofen

    • safe and increases abstinence rates

  • acamprosate and naltrexone

    • possible hepatotoxcity in ALD

Definition

• a common metabolic cause of liver disease in children and adults

• affects ~1:3500 live births

• production of misfolded A1AT protein leads to low A1AT levels in serum (<15% of normal)

• leads to lung damage via unopposed action of pulmonary neutrophil elastase

• liver damage caused by accumulation of abnormal protein in endoplasmic reticulum of hepatocytes causing oxidative damage and eventual fibrosis and cirrhosis

• suspect in any patient with unexplained cirrhosis or unexplained mild AST/ALT elevations

• gold standard of diagnosis is A1AT phenotyping suing isoelectric focusing

  • allows identification of the abnormally folded protein (S or Z forms) instead of the normal protein (M form)

  • patient's with the PiZZ phenotype express 10-20% of the normal A1AT and tend to have the most severe disease

• low serum A1AT can suggest the diagnosis, but this enzyme is an acute phase reactant and A1AT may be falsely elevated

Risk Factors

• Personal or family history of early COPD (before age 50)

Pathology Findings

• Liver biopsy - not needed for diagnosis

  • PAS positive globules within hepatocytes

    • resistant to digestion with diastase

Definition

• liver disease thought to be due to production of thick biliary secretions, similar to thick mucus and pancreatic secretions due to the CFTR mutation

  • obstructs the biliary tree, inducing inflammation and fibrosis

• Diagnostic criteria for CFLD (two out of three)

  • hepatomegaly and or splenomegaly

  • abnormal AST/ALT/GGT

  • ultrasound evidence of cirrhosis or biopsy proven biliary cirrhosis

Signs and Symptoms

• asymptomatic LFT elevations (primarily AST, ALT, and GGT)

• cirrhosis and portal hypertension (occurs in ~5% of cases)

• a small number of children with CF have neonatal cholestasis

  • significant conjugated hyperbilirubinemia

• others have gradual progression to cirrhosis by late childhood

Treatment

• Ursodiol

  • most often used in children with cholestatic liver disease

  • data for benefit in CFLD is not conclusive

Definition

• an inborn error of metabolism

• occurs in 1/100,000 births

• defect in glucose-6-phosphatase

  • cannot break down glycogen into glucose

Signs and Symptoms

• enlarged glycogen-rich liver

• hypoglycemia

• lactic acidosis between feedings

  • manifesting as lethargy and seizures

• significant hyperlipidemia

  • may develop xanthomas

Pathology Findings

• liver biopsy

  • glycogenosis of hepatocytes

Treatment

• frequent feedings either orally or via gastrostomy tube to manage hypoglycemia

• risk of hepatic adenomas remain

  • these may undergo malignant transformation in up to 10%

  • liver transplantation may be considered when HCC is identified

    • leads to correction of much of the metabolic defect

Definition

• a lysosomal storage disease

• autosomal recessive

• caused by mutations in the beta-glucocerebrosidase gene

  • leads to accumulation of glucocerebrosidase in macrophages (liver, spleen, and bone marrow are major sites)

• progression to cirrhosis is rare

• though there is an increased risk of HCC

Signs and Symptoms

• high prevalence in Ashkenazi Jewish populations

• hepatosplenomegaly

• liver enzymes normal or only mildly elevated

• bone fractures

• young age of presentation

Pathology Findings

• Liver biopsy

  • Gaucher's cells - lipid-laden macrophages

  • variable amounts of associated inflammation

Treatment

• Eliglustat

  • leads to decrease in liver and spleen size

Definition

• due to acute lowering of blood flow to the liver

• uncommon condition, 1-3% of ICU admissions

• often called "shock liver" but only 50% have overt shock

  • high index of suspicion required for less obvious decrease in hepatic perfusion

Signs and Symptoms

• RUQ pain

• malaise

• elevated transaminases

  • usually decrease rapidly and normalize within 2 wks

• elevations in bilirubin may persist after transaminases improve

• elevated serum LDH

• only mildly elevated alkaline phosphatase

Pathology Findings

• Liver biopsy

  • hepatocyte necrosis in Zone 3 of the acinus with few inflammatory cells

Treatment

• Supportive care

• restoration of cardiac output and liver perfusion

• no specific drug therapy is recommended

Definition

• rare condition of bile duct injury due to impaired blood supply

Signs and Symptoms

• variable presentation

  • asymptomatic liver enzyme abnormalities (mainly alkaline phosphatase and GGT)

  • progressive cholestasis with jaundice

  • ischemic stenosis of CBD present as acute obstructive jaundice or cholangitis

    • diffuse biliary stricturing post liver transplant should prompt evaluation of hepatic artery flow

Risk Factors

• liver transplantation

  • often seen following transplantation using donation after circulatory death organs

• administration of hepatic intra-arterial chemotherapy

• AIDS cholangiopathy

• polyarteritis nodosa

• hereditary hemorrhagic telangiectasia

Definition

• occurs in 8-25% of patients with decompensated liver disease

  • HCC-related tumor thrombus should be in the differential

  • assess with AFP and further imaging

  • suspect tumor thrombus if endoluminal material enhances during the arterial phase of imaging or if there is evidence of arterial pulsatile flow on doppler ultrasound

• can occur despite thrombocytopenia and/or elevated INR

  • INR reflects liver synthetic function but not degree of hypo/hypercoagulability

  • liver dysfunction decreases levels of natural anticoagulant factors (Proteins C and S, and other clotting factors)

Risk Factors

• cirrhosis

• myleoproliferative disorder (30-40% of cases)

• protein C and S deficiency

• antithrombin deficiency

• Factor V Leiden mutation

• antiphospholipid syndrome

• paroxysmal nocturnal hemoglobinuria

Signs and Symptoms

• abdominal pain

  • may be accompanied by fever or other inflammatory markers

• Clot confined to portal vein

  • symptoms mild-to-moderate

• Extension into SMV

  • intestinal ischemia or infarction may occur

Treatment

• systemic anticoagulation improves outcomes in cirrhotic PVT

  • recanalization rates of 55-75%

  • partial recanalization in and additional 40%

  • should be delayed until variceal bleeding prophylaxis has been implemented with band ligation

  • LMWH or coumadin for at least 3-6 mo with lifelong therapy in those with identifiable prothrombotic disorder

  • too little data on NOACs to recommend at this time

  • re-evaluate with ultrasound for recanalization

Definition

• Isolated gastric varices (IGV1)

  • may be caused by splenic vein thrombosis seen in chronic pancreatitis or after pancreatic surgery

Treatment

• non-selective beta blockers may be used for prophylaxis of gastric variceal bleeding

• IGV1 acute bleeding

  • injection therapy with cyanoacrylate glue

    • in small trials shown to be superior to EVL in initial hemostasis and prevention of early rebleeding

  • in the setting of portal hypertension, TIPS recommended if endoscopic therapy fails

  • Balloon-occluded retrograde transvenous obliteration (BRTO) may be effective to prevent rebleeding

    • feasible only if there are sufficient gastro/splenorenal collaterals which can be seen on CT

    • left renal vein is cannulated

    • splenorenal collaterals and fundic varices are obliterated using sclerosants or coils

    • BRTO may be paired with TIPS to prevent increases in portal pressure after obliteration of collateral vessels