Acute Liver Failure.

Acute Liver Failure

Definition The development of prolonged prothrombin time and encephalopathy within 8 weeks of symptom onset in patient with no previous liver disease U.S. annual incidence about 2,000 cases per year (1) High mortality 1. Hoofnagle JH, Carithers RI, Shapiro C, et al: Fulminant hepatic failure: a summary of a workshop. Hepatology 1995, 21:

Causes of Acute Liver Failure
Varies by geographic region In the U.S., acetaminophen hepatotoxicity most common Indeterminate cause Idiosyncratic drug reactions – Isoniazid most common

Causes of ALF Hepatitis B – U.S. 4th most common cause; world wide # 1 cause Hepatitis A – endemic areas Autoimmune hepatitis Ischemia Wilson’s Disease 2.

Causes of ALF Budd Chiari Syndrome
Pregnancy – acute fatty liver of pregnancy and the HELP syndrome (hemolysis, elevated liver chemistries, low platelets)

Transplant-free Survival
Highest in APAP hepatotoxicity Followed by drug reaction Followed by indeterminate cause Best when ALF develops hyper acutely i.e., within seven days

The Phenomenon Highly unpredictable Dramatic
Requires aggressive intensive care management, anticipation of complications, and evaluation/listing for liver transplantation

Survival Correlates with degree of encephalopathy and coagulopathy
Encephalopathy may be abrupt and rapidly progressive Subtle mood change - > seizures - > obtunded - > decorticate posture Associated with cerebral edema rather than portosystemic shunting of toxins seen in cirrhosis

Acetaminophen Overdose
Accidental Suicide gesture/attempt Emergency Room administration of antidote: p.o. NAC or I.V. Acetadote (contraindicated in sulfa allergy)

Accidental Overdose High dose APAP for an extended period
Inadvertent simultaneous administration of APAP w/ combination drugs: OTC Sinus and cold preparations OTC Narcotic pain relievers OTC Sleep preparations In combination w/ alcohol

Pathophysiology Dose dependent; known liver toxin
Also influenced by the presence of malnutrition, concomitant ethanol, co-administered drugs, and CYP 384 polymorphisms Centrilobular necrosis without inflammation

Signs and Symptoms Anorexia, nausea, vomiting, malaise, right upper quadrant discomfort Dark urine, pale stool, icterus Transaminases rise within 10 – 12 hours, often to dramatic levels AST > ALT, peak at day three and rapidly improve Jaundice develops quickly, total bilirubin not as high as that seen in other causes of ALF

Case Study

Questions and Answers

Cirrhosis and Portal Hypertension
The Final Stage of Chronic Liver Disease Due to Any Cause

Cirrhosis Excess extracellular matrix/fibrosis in liver
Fibrosis spans portal-central areas portal-portal or central-central also seen Fibrosis encases groups of hepatocytes Results in distorted architecture and vasculature

Nodules surrounded by fibrous tissue
Normal Cirrhosis HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER Histological images of two livers. On the left, a normal liver with conserved architecture. On the right, a cirrhotic liver with regenerative nodules surrounded by fibrous tissue (stained blue). Nodules surrounded by fibrous tissue

GROSS IMAGE OF A CIRRHOTIC LIVER
Nodular, irregular surface Nodules GROSS IMAGE OF A CIRRHOTIC LIVER Gross image of a cirrhotic liver demonstrating an irregular surface and nodules that give it a heterogeneous appearance.

Portal Hypertension Cirrhosis - > increased resistance to flow of blood in sinuosoids and in liver Increased resistance = increased portal pressure = portal hypertension Pressure in PV causes release of vasodilators, i.e., nitric oxide (NO) NO causes splanchnic arteriolar vasodilation and increased splanchnic inflow of blood This increased flow maintains portal hypertension in spite of development of low resistance collaterals PV: portal vein

SINUSOIDAL PORTAL HYPERTENSION
Portal systemic collaterals Cirrhotic liver In sinusoidal portal hypertension, the site of increased vascular resistance is the hepatic sinusoid. The most common cause of sinusoidal portal hypertension is cirrhosis where fibrous tissue deposition, active vasoconstriction and nodule formation obstruct the sinusoids and the intersinusoidal communications leading to sinusoidal and portal hypertension. Portal vein

Consequences of Portal Hypertension
Splenomegaly Thrombocytopenia Palpable spleen; splenectomy harmful Varices On imaging may be peri-gastric, esophageal, or splenic On gastroscopy of variable size Risk for bleed increases w/ advancing liver failure Treat w/ nonselective beta blocker, banding

Ascites: The accumulation of fluid in the peritoneal cavity An important clue to the presence of advanced cirrhosis Result of sinusoidal HTN caused by blocked hepatic venous outflow 2/2 regenerative nodules and fibrosis Result of plasma volume expansion, sodium, and water retention

Serum to Ascites Albumin Gradient “SAAG”
The concentration of ascitic fluid protein is much lower than the concentration of serum protein This is due to sinusoidal capillarization, decreased permeability to plasma proteins Protein concentration in ascitic fluid in cirrhosis correlates inversely w/ the degree of portal hypertension

Ascites Associated conditions: Complication of ascites: Hyponatremia
Umbilical hernia Hepatic hydrothorax Complication of ascites: Spontaneous bacterial peritonitis Pneumococus common etiology Gram negative bacteria

Ascites Treatment: Sodium restriction, diuretics, paracentesis Transjugular intrahepatic portosystemic shunt TIPS often worsens encephalopathy Prognosis: continuum of uncomplicated ascites - > refractory ascites - > hepatorenal syndrome Mortality approximately 20%/year

THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT
vein TIPS Portal hypertension can be corrected by creating a communication between the hypertensive portal system and low-pressure systemic veins, bypassing the liver, i.e., the site of increased resistance. This communication can be created surgically or by the transjugular placement of an intrahepatic stent that connects a branch of the portal vein with a branch of an hepatic vein, a procedure designated transjugular intrahepatic porto-systemic shunt (TIPS). TIPS is performed by advancing a catheter introduced through the jugular vein into a hepatic vein and into a main branch of the portal vein. An expandable stent is then introduced connecting hepatic and portal systems, and blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein. The procedure is highly effective in correcting portal hypertension but can be associated with complications related to diversion of blood flow away from the liver, namely portal-systemic encephalopathy and liver failure. Splenic vein Portal vein Superior mesenteric vein

Hepatic encephalopathy Episodic vs persistent Usually precipitated by events such as: Bleeding Infection Use of sedatives or hypnotics Dehydration

Hepatic Encephalopathy
Pathogenesis: failure of the liver to detoxify portal blood toxins in the setting of decreased hepatic function and/or diminished hepatic perfusion by portal blood. Cerebral edema, ammonia, and disturbances in cell function, esp. astrocytes Diagnosis: don’t assume it is HE until other potential causes of altered mental status have been considered

Encephalopathy Alternative Explanations
Metabolic: hypoxia, hypoglycemia, hypo/hypernatremia, thyroid disease, hypercalcemia Central Nervous System: CVA, Subdural hematoma, post ictal state, metastatic cancer Toxins: alcohol, CNS depressants Infection: sepsis, meningitis, encephalitis, delerium tremens

Staging West Haven Criteria
Stage 0: No abnormality Stage 1: Trivial lack of awareness Shortened attention span Euphoria or anxiety Impairment of addition and subtraction Stage 2: Lethargy Time disorientation Personality change Inappropriate behavior

Staging Hepatic Encephalopathy West Haven Criteria
Stage 3: Somnolence to semistupor Response to stimuli Confusion Disorientation Bizarre behavior Stage 4: Coma Generalized motor abnormalities common: hyperreflexia, asterixis, Babinski +

Hepatic Encephalopathy
Blood ammonia testing has little role in the diagnosis of HE Clinical suspicion is the main guide Treatment: Supportive care for altered mental state Identify and treat the precipitating cause Exclude and/or treat other medical illnesses Begin empirical therapy: lactulose, nonabsorbable antibiotics, metronidazole

Complications of Cirrhosis
Osteoporosis Increased risk of infections Muscle cramps Increased risk for hepatocellular carcinoma Malnutrition Depression Pruritis

Standard Recommendations for All Cirrhotics
Vaccinate against viral hepatitis, pneumococcal pneumonia, influenza Baseline bone density test – treat osteopenia or osteoporosis as indicated Baseline ultrasound and AFP and repeat semi-annually for HCC surveillance if cirrhotic Esophageal varix surveillance – treat as indicated AFP: alpha fetoprotein HCC: hepatocellular carcinoma

Standard Recommendations for All Cirrhotics
Refer for liver transplantation Monitor for signs of advancing liver failure Avoid alcohol Avoid NSAIDs Acetaminophen is analgesic of choice If significant ascites, cane, walker If Grade II or higher encephalopathy take the car keys, protect from harm

Case Study

Prototype Chronic Liver Disease
Hepatitis C Prototype Chronic Liver Disease

History of Viral Hepatitis
2000 B.C. 1st recorded hepatitis epidemic 1963 Australia antigen AKA Hepatitis B surface antigen (Blumberg & Alter) 1970 Hepatitis B 1972 National Blood Policy requires testing of blood donors for HBsAg

History of Viral Hepatitis
1973 Hepatitis A (Feinstone, Kapikian & Purcell) 1975 “Non-A Non-B Hepatitis” 1977 Hepatitis D (Rizzetto & Gerin) 1983 Hepatitis E (Balayan) 1989 Hepatitis C (Alter, et al. & Chiron Corp)

Disease Burden Estimates Center for Hepatitis C, Cornell University
HIV HBV HCV US Chronic Infection 1.0 million million 3-4 million* New Infection/year 40,000 50,000* 20-30,000 Deaths/year 16,000* 3,000-5,000 10,000 – 12,000 Worldwide Chronic Infection 40 million 350 million* 1/3 world population 170 million 4 million 65 million* 3-4 million 3 million* 0.5 – 1.2 million >250,000

Hepatitis C Prevalence Estimates
Affects both genders, all ages, races and regions of the world: 170 million or 3% world population 40% of all chronic liver disease in U.S. Most common blood-borne infection in the U.S.: 1.8% of population 5.2 million HCV antibody positive, 4.1 million HCV RNA+ 1.1 million = homeless, incarcerated, institutionalized, undocumented, and military U.S. prisons estimates: 600,000 HCV RNA+ 25% - 40% of prison population 30% released each year (high risk behavior perpetuates transmission) Born between 1945 and 1964, now age 55-64, have highest mortality

Estimated Incidence of Acute HCV Infection United States, 1960-2001
Source: Hepatology 2000;31:777-82; Hepatology 1997;26:62S-65S; CDC, unpublished data

Hepatitis C Facts HCV related deaths increased 123% between (Wise, et al.) 1.09 deaths per 100,000 in 1995 2.44 deaths per 100,000 in 2004 In 2004: 7,427 deaths, male 2.5 x > female Middle-aged cohort 45 y/o to 64 y/o Male Hispanic, AA, NA, Alaska natives African American males 9% w/ HCV-1 Hepatology, April, Based upon U.S. Census and multiple cause of death data.

Hepatitis C Facts Less than 10% of infected are being treated
Most do not know they are infected 85% of HCV positive individuals can be identified by testing year olds with elevated ALT and history of IDU or blood transfusion before 1992 Those infected for 20 – 30 years 10% - 20% -> cirrhosis 1% - 5% -> hepatocellular carcinoma

Who to Screen Ever injected drugs Clotting factors before 1972
Received organ before 1992 Ever on dialysis Children of infected mothers Evidence of liver disease Workers after needle stick injury

Who Not to Screen Non-sexual household contacts
Healthcare workers, emergency medical workers, public safety workers Pregnant women If have contraindication to treatment If have limited life expectancy

Hepatitis C Virus An enveloped, single-stranded, RNA virus with a genome of about 9,600 nucleotides (1 pentose sugar, 1 base + phosphoric acid = structural unit of nucleic acids i.e., RNA and DNA) Flaviviridae family; other viruses in the family include West Nile virus; others cause yellow fever, dengue

Hepatitis C Virus Viral replication 1011 to 1012 virion/day (trillions!) No proof reading ability -> high rate of mutation helps it to escape the immune system -> difficult to eradicate

Genotype: Genetic Sequence
Used to project response to treatment Six types, multiple subtypes

Hepatitis C Around the World
1: 60% U.S. cases; (Europe, Turkey, Japan) 2: 10% - 15% U.S. cases; wide distribution 3: 4% to 6% U.S. cases (India, Pakistan, Australia, Scotland) 4: < 5% (Middle East, Africa) 5: < 5% (South America) 6: < 5% (Hong Kong, Morocco)

Following Exposure Two weeks: HCV RNA detectable
Between weeks 2-4: ALT elevated with spike by week 6 6-7 weeks: Anti-HCV/HCV Antibody detectable T Shaw-Stiffel, 2004 p. 35

Routes of Transmission
Percutaneous Permucosal Household

Percutaneous Exposure
Highest rate is among injecting drug users 80%-90% of cases Recipients of clotting factors prior to 1987 (before virus inactivation) Hemophiliacs Blood transfusion, transplant prior to 1992

Contaminated equipment, unsafe injection practices Hemodialysis, plasmapheresis, phlebotomy Multiple dose injection vials – Las Vegas, NV 2008 Therapeutic injections Treatment of schistosomiasis in Egypt

Occupational Exposure Needle stick with hollow bore needles Incidence 1.8% with exposure to HCV+ source 10 X lower than from HBV + source Case reports: transmission from blood splash to eye Prevalence 1-2% among health care workers (same as general population)

Peter Gulick D.O., Rule of Three’s
Risk of viral transmission following occupational needle stick injury: 30% hepatitis B 3% hepatitis C .3% HIV Peter Gulick is professor and infectious disease physician at Michigan State University, East Lansing, Michigan

Post-Hepatitis C Exposure
Test source for HCV Antibody (anti-HCV) If positive, test worker No post exposure IgG or anti-viral Rx ALT and anti-HCV at baseline and 4 – 6 months For earlier diagnosis, HCV RNA by PCR 4 – 6 weeks Confirm all anti-HCV + result w/ RIBA Refer infected worker to specialist for medical evaluation and management

Route of Transmission Permucosal Inefficient
Perinatally: 5% risk Higher if woman co-infected with HIV No association with delivery method/breast feeding Infected infants: If test for anti-HCV at birth will be positive due to placental transfer; best to test for HCV RNA 3rd or 4th month; often clear by two years, others develop CHC; refer to pediatric specialist

Permucosal - Inefficient
Sexual: 1.5% in monogamous relationships Accounts for 15% - 20% of acute and chronic infections in U.S. Factors that facilitate transmission unknown Infected partner, multiple partners, early sex, non use of condoms, other STDs, sex with trauma MSM no higher risk than heterosexuals Partner studies report low prevalence (1.5%) among long term partners

Route of Transmission Household Contact
Rare Could occur through percutaneous or mucosal exposures to blood Sharing personal hygiene items Contaminated equipment used for home injections, folk remedies, cultural practices such as scarification, circumcision, tattooing Adapted from Hepatitis Slide Kit Accessed 4/20/08

Natural History Clinical spectrum is variable and disease progression is unpredictable. Majority develop chronic hepatitis C: HCV Ab+, RNA by PCR+ Mild - majority Moderate Severe T Shaw-Stiffel, 2004 p. 35.

Natural History Acute Hepatitis C
Frequently asymptomatic Symptoms: malaise, asthenia, anorexia, right upper quadrant discomfort, pruritis, less common jaundice (25%), intermittent nausea, vomiting. 1/6 seek medical attention Usually resolves in 12 weeks Rates of spontaneous clearance between 15% to 45% Loss of virus between 6 and 24 months

Factors Influencing Progression
Host Factors Virus Factors Environment

Host Factors Age at infection: 40 y/o and older, more severe disease Male gender: less likely to clear virus Obesity/Non Alcoholic Fatty Liver Disease Immune system status ? Genetic susceptibility

Viral Factors Co-infection with HBV, HIV Duration Transfusion related CHC leads to more aggressive disease (CABG age 50, time to cirrhosis 14.7 years) IDU age 40: 16 years to cirrhosis Less than age 50: 29.2 years to cirrhosis IDU age 21-30: 33 years to cirrhosis

Environmental Factors Alcohol consumption suppresses immune response hepatotoxic promotes fibrogenesis 50g/day men, 20g/day women Antiviral Therapy Iron – Genetic Hemochromatosis

Natural History Chronic Hepatitis C
Mild – infection 40 years or more with no or mild fibrosis Moderate – Severe cases progress to: Cirrhosis End Stage Liver Disease Hepatocellular carcinoma Liver transplantation Death

Chronic Hepatitis C Frequently no symptoms until development of advanced liver disease Fatigue, depression, cognitive changes (difficulty concentrating, memory impairment) Extra hepatic manifestations

As Soon as Diagnosis Confirmed
Immunize against hepatitis A and hepatitis B Advise patient to avoid alcohol Review all medications, including over the counter, vitamins, herbal remedies, and nutritional supplements for potential hepatotoxicity Teach transmission risk reduction strategies

Barriers to Treatment Stigma – people unwilling to discuss
Treatment options: toxic, costly, overall sustained virological response (SVR) 55% Access to care: collaborative approach should include PCP, specialist, case manager, qualified mental health provider, substance abuse trained provider No public funds for screening, surveillance, prevention programs, treatment, community- based needle exchange programs PCP primary care provider

Barriers to Treatment Substance abusers mistrust authorities, unpredictable follow through, lack of experience w/ the healthcare system Provider: Inexperience, ignorance Unrealistic expectations, resource intense Negative attitude Frustration Moralize Patient blame

History of HCV Treatments
1991: 1st generation was interferon alpha 1998: 2nd generation ribavirin added to interferon alpha (increased SVR from 16% to 41%*) Virazole developed 1972 for influenza Viramidine the pro-drug of ribavirin RVN is a nucleoside analog 2001: 3rd generation pegylated interferon replaces interferon alpha *McHutchison JG, Manns MP Brown RS et al, AJG 2007;102:

Factors Influencing Response to Treatment
Host Factors Race Steatosis, obesity Cirrhosis 10% to 12% lower rate of SVR Immunocompromised Virus Factors Genotype Viral load Early viral kinetics Therapeutic Presence of rapid virological response Inadequate dosing Non-compliance

Goals of Therapy Viral Eradication: sustained virological response
Genotypes 1,4,6 45% SVR Genotypes 2 & 3 70% to 85% SVR Improve Histology Prevent decompensation Reduce rates of HCC Reduce need for transplantation Prevent liver-related death

Treatment Considerations
Stage of liver disease Likelihood of SVR Co-morbidities Social support Presence of extra-hepatic manifestations Age, motivation

Who is Eligible for Treatment?
Any person infected with hepatitis C is a potential candidate The majority will not progress to cirrhosis and its complications: 20% will progress to cirrhosis in 20 years If no contraindications, treat genotypes 2 and 3 without liver biopsy Perform biopsy on genotype 1

Who is Eligible for Treatment? (cont’d)
If no fibrosis may choose to delay Treatment often not urgent Patient should determine timing

Contraindications to Treatment
Uncontrolled or severe depression Active alcohol/substance abuse Decompensated liver disease Renal transplant

Liver Biopsy Liver biopsy is to hepatitis C as CD4 count is to HIV
Grade indicates the extent of necro-inflammatory damage Stage indicates the cumulative fibrosis damage Confirm clinical diagnosis Evaluate possible concomitant disease Assess therapeutic response

Liver Biopsy 20% sampling error Tendency to under stage fibrosis
Pathologist inter-individual variability, experience Not without risk Pain Bleed Perforated viscous

Treatment Pegylated interferon SQ weekly with ribavirin PO twice daily for 24 to 48 wks Difficult. Fatigue universal Common adverse effects: Flu like symptoms fever, myalgia, cephalgia Nausea, diarrhea, weight loss – 1/3 Irritability, anxiety, anger, insomnia, impaired concentration 1/3 Depression – severe in < 1:1,000 Rash, pruritis, alopecia

Treatment—Adverse Effects
Neutropenia, anemia, thrombocytopenia – growth factors and/or dose reduction may be required Retinopathy - rare Immune mediated disorders < 1% Thyroid, diabetes, psoriasis, neuropathy Teratogenic – protection against pregnancy required

Monitoring While on Treatment
Significant other/caregiver to help pick up changes in mood that require treatment Frequent phlebotomy, office visits Look for side effects and treat Some side effects diminish w/ time Hydration, healthy diet important Medication compliance crucial Sleep hygiene

Future of Hepatitis C Treatments
Protease inhibitor: VX-950/Telepravir SCH /Boceprevir Polymerase inhibitor: R 1626 complicated by ADE i.e., Stevens-Johnson’s syndrome, neutropenia These agents will be add-on to overcome mutations and subsequent resistance

Summary Hepatitis C is epidemic Most don’t know they are infected
Treatment is difficult, but most can handle it with appropriate support systems in place and careful monitoring Hepatitis C is the driving force behind the rise in cases of HCC New treatments on the horizon purport to shorten treatment duration

References Wise M, Bialek S, Finelli L, Sorvillo F. Changing trends in hepatitis C-mortality in the United States Hepatology; 47,4:

Extrahepatic Manifestations of Hepatitis C
Cryoglobulinemia Clinical triad of purpura, arthralgias, weakness May affect kidneys, peripheral nerves, or brain Membranoproliferative Glomerulonephritis Porphyria cutanea tarda Leukocytoclastic vasculitis Itskowitz MS, and Babich MM. Hepatitis C. Emerg Med ;36(7):36-42 Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus infection and HCV-related chronic disease. MMWR Recomm Rep. 1998;47(RR-19):1-39.

Sicca syndrome/Sjogren’s syndrome Sero negative arthritis Autoimmune thyroiditis Idiopathic pulmonary fibrosis (Hamman-Rich syndrome) Polyarteritis nodosa Lichen planus

Mooren’s corneal ulcer Aplastic anemia Overt B-cell lymphomas Psychological disorders, including depression Osteosclerosis Higher incidence of non-Hodgkin’s lymphoma, thyroiditis, diabetes mellitus

Nonalcoholic Fatty Liver Disease
A Growing Epidemic

NAFLD A Continuum Simple steatosis – a benign condition
May progress to steatohepatitis – > fibrosis - > cirrhosis - > hepatic decompensation - > liver failure - > premature death without liver transplantation

Natural History of NAFLD
Simple steatosis affects 60% of the obese These individuals will not progress to steatohepatitis and cirrhosis Where is the fat in fatty liver?

Obesity An Epidemic

Obesity NHANES data 2003-2004 shows:
32% of U.S. adults aged > 20 are obese 17% U.S. children and teens are overweight Becoming one of the most important chronic liver diseases in children and adolescents Affects 2.6% to 9.8% of this young population, up to 77% of the obese. 1 Rapid progression to cirrhosis in some children and young adults

Obesity Defined “Just right”: Adult w/ body mass index (BMI) 20 to 25 kg/m2 Overweight: BMI 25 to 29.9 kg/m2 Obese: BMI > 30 kg/m2 Morbid obesity greater than 35 NHANES National Health Examination Survey

Natural History of NAFLD
20 – 25% will develop the progressive form of NAFLD, called “Nonalcoholic steatohepatitis” (NASH) One of the most common liver diseases in the developed world 15% will progress over five years to cirrhosis Cirrhosis increases risk of Hepatocellular Carcinoma Greater w/ increasing BMI Male > Female

Risk Factors for NAFLD Waist : hip ratio > .9 in males, > .85 in females (apple shape), BMI > 30 Medications: amiodarone, tamoxifen, corticosteroids, estrogens, agents used in treatment of AIDS indinavir Severe weight loss, i.e., jejunoileal bypass Metabolic syndrome

The Metabolic Syndrome
About 47 million U.S. adults affected 1 million 12 to 19 year old adolescents World Health Organization definition of the metabolic syndrome: BP: > 140/90, hyperglycemia, high waist to hip ratio, triglyceride > 150 and/or low HDL NAFLD, NASH are the hepatic manifestation of the metabolic syndrome American Heart Association Heart disease and stroke statistics-2006 update. Circulation;113:e

Epidemiology NAFLD prevalence 3-6 NASH prevalence:
17% to 33% of U.S. adults Bariatric surgical candidates 84% to 96% NASH prevalence: 5% to 17% Bariatric surgical candidates 25% to 55% CIRRHOSIS prevalence: 0.8% to 4.3% Bariatric surgery patients 2% to 12%

Pathophysiology Obesity and fatty liver are often accompanied by a chronic, low grade inflammatory state mediated by the immune system The pro inflammatory cytokines tumor necrosis factor alpha, interferon beta, interleukin-6, C reactive protein, and other acute phase proteins are released by adipocytes and macrophages Evidence suggests that the inflammatory response itself may be responsible for insulin resistance and cardiovascular disease

Pathophysiology In the liver, Kupffer cells release cytokines that activate stellate cells to begin forming scar tissue (fibrogenesis) Oxidative stress enhances insulin resistance; however, antioxidants, i.e., vitamin C and vitamin E have not been shown to improve hepatic histology

Diagnosis of NAFLD In the U.S. NAFLD is the most common cause of elevated transaminases. ALT usually > AST Persistent elevation of AST and/or least 1.5 x ULN for six months Exclusion of other causes of liver disease Ethanol consumption < 140g/wk in men, < 70 g/wk in women

Diagnosis of NASH NASH is a tissue diagnosis
Liver biopsy required (unless “cryptogenic” cirrhosis already present) Biopsy can accurately diagnose NASH, exclude other causes of liver disease, stage, and determine prognosis Consider when age > 45, need to gain commitment to treatment If cirrhosis, consider referral to hepatologist

Histology Features of NAFLD include: Steatosis (0-3)
Hepatocyte ballooning (0-3) Lobular inflammation (0-2) Fibrosis (0-4) Grade of necroinflammatory change is scored from 0–8 Stage of fibrosis is scored 0-4

Management No approved pharmacotherapy at this time, though active research is ongoing Control diabetes, hypertension, dyslipidemia. Therapeutic lifestyle changes are the cornerstone of management Extremely resistant to treatment; dietician consultation critical Discourage rapid weight loss (can worsen liver disease)

Case Study Middle-aged female BMI 31.4 95
< .9 Non-drinker DM-2 on oral agents Viral hepatitis panel negative, normal platelet count and albumin Right Upper Quadrant Ultrasound suggests fatty infiltration of liver

Case Study 30 y/o M BMI 34 Alcohol consumption about 24g/day
No previous hepatitis B immunization Family history of diabetes, coronary artery disease Takes no regular medications or supplements

Case Study (cont.) 54 --------------/------< .8 79 120
Ultrasound normal Stops all alcohol and repeat LFTs show: 49 /------< .7

References Nobili V, Manco M, Devito R, et al. Lifestyle intervention and antioxidant therapy in children with non alcoholic fatty liver disease: A randomized controlled trial. Hepatology 2008;48: Fortson J, Howe L, Harmon C, & Sherrill WW. Targeting cardiovascular risk: Early identification of insulin resistance. Journal of the American Academy of Nurse Practitioners 2008; Diehl AM. Hepatic complications of obesity. Gastroenterology Clinics of North America 2005;34:45-62.

References 4. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. Journal of Clinical Gastroenterology 2006;40(3 suppl 1):S5-S10. 5. Sanyal AJ. Gastroenterological Association technical review on nonalcoholic fatty liver disease. Gastroenterology 2002;123: 6. MCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. Journal of Clinical Gastroenterology 2006;40 (3 suppl 1):S17-S29.

References 7. Jonson JR, Barrie HD, O’Rourke P, Clouston AD and Powell EE. Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C. Hepatology 2008;48:80-87.

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