Case Conference January 5th, 2015

Transcription

1 Case Conference January 5th, 2015

2 53 year old man CC: Turning yellow PMH Type 2 DM Hyperlipidemia Chronic Back Pain Meds (Stopped 6 months ago) Glipizide Metformin Simvastatin Gabapentin Aspirin Lisinopril Furosemide Social History Single On disability 36 oz/wk of ETOH for years Drinks mostly vodka 40 pack year smoking history Family History Father: CAD Mother: Colon cancer Sister: Healthy

3 HPI One week history of: Feeling tired Poor appetite but very thirsty Increased urinary frequency Has appt scheduled with PCP in 1 month (couldn t get in sooner) Mother & sister visited 3 days PTA and noticed that he looked yellow They convinced him to seek care sooner, so now coming to ED Additional ROS: Early satiety for 1 month Unintentional weight loss of pounds over the past 2 years Dark urine for the past 2 wks Intermittent subjective fevers No SOB No CP or edema No N/V/D No abdominal pain No constipation or stool color changes Questions

4 Exam BP 98/64 P 95 T 98.5 F RR 24 Ht 6 2 Wt 332 lb SaO2 100% General: NAD Eyes: Scleral icterus HEENT: Poor dentition Resp: Clear CV: Distant heart sounds, RRR, no M/R/G, no JVD or edema Abd: Obese, distended, non-tender, dull to percussion, could not palpate liver Lymph: No LAD Skin: Diffuse jaundice; spider nevi on face Neuro: A&O, no focal deficits

5 T-I-N-C-H-E-M-P-V-I Albumin 2.8 Total Protein 6.3 Total Bilirubin 38.2 Direct Bilirubin 16.2 Indirect Bilirubin 22 Alk Phos 332 ALT 40 AST 141 INR 1.4 Lipase 33 Amylase 12

6 What would you guys like next? ERCP? US? CT abd/pelvis? MRI? HIDA? Ultrasound Considerable hepatomegaly with increased echogenicity most commonly associated with fatty infiltration No gross biliary obstruction Splenomegaly cm CT abdomen/pelvis Hepatomegaly & liver fatty infiltration No extrahepatic biliary dilatation Contracted gallbladder, not overtly inflamed

7 GI Consult Bilirubin too high to be obstruction Findings are consistent with severe alcoholic hepatitis + Factors: preserved renal function, near normal INR - Factors: high bilirubin, low sodium Does have risk factors for fatty liver Defer biopsy as would not alter course at this point

8 Hospital Days 2-4 Started on lactulose due to asterixis GI recommended deferring prednisolone Serologies negative HAV, HBV, HCV HIV negative Bilirubin stable in mid 30s Liver biopsy Cholestatic steatohepatitis Marked steatosis Moderate inflammatory activity (grade 2 of 3) Moderate pericentral & periportal fibrosis (stage 2 of 4) No superimposed liver disease

9 Hospital Days 5-17 Hospital Day 5 Cr 0.9 -> 1.5 -> 2.6 over 3 days Na 129 -> 125 Renal consulted: felt patient was likely dry Hospital Day 6 Cr 2.6 > 3.1 UOP Decreased Renal: now consistent with Type 1 hepatorenal syndrome MELD score 40 (83% 90 day mortality) Midodrine, prednisolone & octreotide Hospital Days 7-11 Cr 6.9 Bilirubin peaked at 46.8 Patient intermittenty encephalopathic Care Conf: proceed with HD Hospital Day 17 INR 2.6 Bilirubin down to 34

10 Final Course Tolerated dialysis LFTs & lytes stabilized Discharged to home with plans for HD T-Th-Sat Readmitted 2 months later with line sepsis (enterococcus) HD discontinued Renal function normalized (Cr 1.3) Bilirubin normal Transaminases normalized

11 Alcohol Related Liver Disease (ALD) Plus some stuff on cirrhosis & all the complications

12 Board Question 50 yro man is evaluated during a routine visit for alcoholic cirrhosis. He has a 3 month h/o hepatic encephalopathy, characterized by forgetfulness & personality changes, that is well controlled with lactulose. He has not consumed alcohol in the last 2 years. One year ago he developed ascites that required diuretics. At that time a screening upper endoscopy revealed no varices. His current medications are lactulose, spironolactone, and furosemide. On exam, he is alert and in NAD. He is oriented but has a mild psychomotor slowing. Vitals are normal. Scleral icterus, temporal wasting, and spider angiomata are noted. Neuro exam reveals mild asterixis. Labs: Hct 33%, Platelets 75,000, INR 1.4, Albumin 2.9, ALT 32, AST 45, Bili 4, Cr 1.3, Lytes normal. Which of the following is the most appropriate management? 1. Add nadolol 2. Begin a low protein diet 3. Continue medical treatment without changes 4. Refer for liver transplantation He has manifestations of decompensated liver disease. These individuals have higher mortality rates and all should be evaluated for liver transplant

13 How does alcohol damage the liver? Our understanding of the pathogenesis is incomplete Alcohol is a direct hepatotoxin It initiates a variety of metabolic responses that influence the final hepatotoxic response Thought to begin with the production of toxic protein aldehyde products (which promote lipogenesis, inhibit fatty acid oxidation) Results in a host of cytokine release causing liver injury TNF whoops in to help facilitate hepatocyte apoptosis & necrosis More cells get activated to make collagen > causes fibrosis Fibrosis affects the liver architecture & progression leads to cirrhosis

14 Alcohol Related Liver Diseases ALD Steatosis Alcoholic Hepatitis Cirrhosis And lastly the late stage consequence of cirrhosis HCC

15 Alcohol Related Liver Disease Abuse can lead to: Fatty liver (steatosis) Alcoholic Hepatitis Cirrhosis HCC Occurs w/in 2 weeks of regular alcohol use (common) Resolves in 4-6 wks with abstinence If persistent use: ~1/3 will develop steatohepatitis 30% risk of progressing to cirrhosis Histo: same as NAFLD Acute form of liver injury Usually heavy use (>100g/d) for 20+ yrs Range of severity (asypmtomatic transaminitis to fulminant liver failure) Poor short term prognosis Risk for decompensation (ascites, variceal bleeding, encephalopathy) Once decompensated, 5 yr transplant free survival is 60% if alcohol free vs. 30% if drinking 80% of HCC cases occur in patients with cirrhosis Need to screen with US q6mo

16 Not everyone gets ALD But once it develops, continued use typically leads to persistent & often progressive liver disease Both binge & chronic drinkers are at risk Development is directly related to amount of alcohol consumed Risk Factors Ethanol Ingestion (30 + g/d) Coexisting Hep B or C Females Obesity Iron Overload states Hispanic/American Indian

17 Alcohol Related Liver Disease Clinical Manifestations Fatty liver (steatosis) Alcoholic Hepatitis Cirrhosis HCC Asymptomatic Exam is generally normal, but may also have hepatomegaly Can be jaundiced or have mild fever and RUQ pain Anorexia, proximal muscle wasting Hepatomegaly (+/- tender) Peripheral stigmata of liver disease Signs of hepatic decompensation (ascites, edema, encephalopathy ) Again, manifestations are variable (asymptomatic to fulminant liver failure)

18 Alcohol Related Liver Disease Lab Tests Fatty liver (steatosis) Alcoholic Hepatitis ALT and AST may be Elevated AST & ALT normal or moderately (can last months) elevated Elevated alk phos & Elevated alk phos & GGT GGT Elevated bilirubin Leukocytosis Classic finding is AST > ALT (ratio > 1 & classically >2) AST is usually < 8x ULN (<500) and ALT is usually < 5x ULN (<200) Degree of elevation does not correlate with severity of disease Alk phos generally not >2/3 ULN (if higher, consider cholestatic liver disease such as PSC or PBC ) Cirrhosis ALT and AST may be normal or moderately elevated Elevated alk phos, GGT Elevated bilirubin (decompensated) Low albumin Elevated INR Elevated Cr (HRS) Hyponatremia Other tests that can be seen in all forms of ALD Low platelets Anemia Elevated MCV Low Lymphos High ESR High INR

19 The History How much alcohol is too much Average consumption of >210g of alcohol per week in men Average consumption of >140g of alcohol per week in women Over a 2 year period FYI: an average drink is 14 grams of alcohol 12oz of beer, 5 oz of wine, 1.5 oz of 80 proof spirits Translates to >15 drinks/week for men & >10 drinks/week for women Those drinking >30g / day - increased risk for cirrhosis Definition c/w 2012 joint guideline from Am. Gastroenterological ASsoc, Am. Assoc for the study of liver disease, & Am College of Gastroenterology The Questions ETOH use (including patterns, type, amount) Medications (herbals & OTC) Parental exposures to viruses (transfusions, IVD, tattoos, sex) Occupational exposures to hepatotoxins Family hx of liver disease Metabolic syndrome, Celiac disease, Autoimmune Disorders

20 Diagnosis Suspected in patient with a compatible hx who has elevated transaminases & suggestion of fatty liver on imaging 2010 guideline from American Association for the Study of Liver Diseases and American College of Gastroenterology & 2012 guideline from European Association for the Study of Liver Obtain detailed hx (ETOH use, evaluate for other causes) Physical exam to ID stigmata of chronic liver disease Lab tests to look hepatic inflammation & to assess synthetic function Transaminases, bili, Alk Phos, GGT, CBC, Albumin, Coags (INR) Lab tests to ID other causes of chronic hepatic injury Hep B surface Ag, anti-hep B core IgG, Abs to HCV Serum ferritin Total IgG or gamma-globulin level, ANA, Anti-smooth muscle Ab, antiliver/kidney microsomal-1 (anti-lkm-1)

21 Diagnosis Continued Just a few words on extra stuff Liver imaging May provide evidence of hepatic steatosis or cirrhosis But can t differentiate alcoholic liver disease from other causes US is ALWAYS indicated to evaluate the liver & to exclude other causes of abnormal liver tests (is biliary obstruction or hepatic masses) US detects steatosis, but misses those with <30% steatosis (fat appears hyperechoic, fibrosis reveals coarse echo texture, and cirrhosis may shows nodules causing irregular liver outline) Biopsy May be required if diagnosis remains uncertain It can also establish the severity of disease

22 Differential Diagnosis Nonalcoholic steatohepatitis Acute viral hepatitis Drug induced liver injury Alpha-1 antitrypsin deficiency Wilson s disease Hemochromatosis Ascending cholangitis Autoimmune hepatitis Decompensation associated with HCC

23 Assessing Severity of Alcoholic Hepatitis Several models have been proposed to assess severity of alcoholic hepatitis But the MDF & MELD are most commonly used Also helpful to predict prognosis / mortality & are used to determine who needs treatment Maddrey Discriminate Function = 4.6 (Patients PT - Control PT) + T bili MELD score = [0.957 (serum Cr) (serum bili) (INR)] * 10 If on hemodialysis (automatically set Cr to 4.0) MDF >= 32 has HIGH short term mortality (as high as 50%) & should be treated with steroids MELD (???): MKSAP says a score of 18+ has similar prognostic implications as the MDF

24 Mortality Factors associated with increased mortality: Older age AKI Elevated bilirubin level Elevated INR Leukocytosis Alcohol consumption >120 g/day Presence of infection (sepsis, SBP, PNA, UTI, aspergillosis) Hepatic encephalopathy UGIB A bilirubin to gamma glutamyl transferase ratio >1 High hepatic histology Rarely: extremely high WBC (leukemoid reaction) - high mortality rates

25 Which patient should be started on corticosteroid therapy? 1. All patients with alcoholic hepatitis 2. Mild to moderate alcoholic hepatitis only 3. Severe alcoholic hepatitis only 4. Steroids have not been proven to improve outcomes in patients with alcoholic hepatitis

26 Treatment for ALD Abstinence Essential to prevent progression & improve survival Steatosis will resolve Portal pressures & Ascities will also improve or normalize More likely among those who receive treatment for alcohol abuse or dependence Nutrition Almost all patients have some degree of malnutrition (protein - calorie malnutrition) Degree of malnutrition correlates with mortality (increased risk for infection, ascites, & encephalopathy) All should have a nutritional assessment Nutritional therapy is indicated for alcoholic fatty liver + malnourished &/or vitamin/mineral deficiencies If not malnourished & no vitamin/mineral deficiencies: encourage healthy, balanced diet Measures to prevent superimposed injury (vaccinate against Hep A & B)

27 Additional Treatments for Alcoholic Hepatitis General Principles for all cases Treat withdrawal Hemodynamic Caution with over-hydration May worsen ascites, cause variceal hemorrhage Nutritional support Thiamine, folate, pyridoxine Phosphate & magnesium Tube feedings if unable to meet caloric needs Infection surveillance If febrile, obtain cultures If Fever + HE, hold on LP unless no improvement with lactulose Prophylaxis aginst GI bleeding (PPI) For severe hepatitis ONLY(MDF >= 32) Corticosteroids Pentoxyfylline Liver Transplant

28 Additional Treatments for SEVERE Alcoholic Hepatitis Corticosteroids Prednisolone 40mg/day x 28 d Finish with 16 d taper Contraindications: Active bacterial/ fungal infection Chronic Hep B/C Pancreatitis, Renal Failure, or GIB (hasn t been studied) Pentoxyfylline Phosphodiesterase inhibitor that also inhibits TNF synthesis Alternative to steroids Use for cases when steroids are contraindicated 400mg TID x 28 d (does need to be adjusted for CKD) Liver Transplant Those with active alcoholic hepatitis are typically not candidates High risk for morbidity & mortality & also higher risk for relapse Most centers require 6+ months of sobriety + enrollment in alcohol rehab program Refer patients with manifestations of decompensated liver failure (ascites, HE, varices) should be referred to transplant center (estimated 50% mortality rate at 2 yrs)

29 Note: Prednisolone is favored over prednisone Prednisone has to be converted to active prednisolone by the liver. This process may be impaired in liver disease

30 Cirrhosis A late stage of progressive hepatic fibrosis Characterized by distortion of hepatic architecture & formation of regenerative nodules Generally irreversible in its advanced stages Develops due to chronic hepatic inflammation or cholestasis MCC in developed countries include chronic viral hepatitis (B/C), Alcohol, Hemochromatosis, and Non-alcoholic fatty liver disease Less common causes: Autoimmune Primary & secondary biliary cirrhosis Primary sclerosing cholangitis Meds (MTX, INH) Wilson disease Alpha 1 Antitrypsin deficiency Celiac disease Granulomatous liver disease Idiopathic portal fiborsis Polycystic liver disease Infection (brucellosis, syphillis, echinococcosis, schistosomiasis) Right sided HF Herediatry hemorrhagic telangiectasia Veno-occlusive disease

31 Clinical Manifestations of Cirrhosis Jaundice / Conjunctival Icterus Ascites (30%) / Abdominal distension Anorexia / Weight loss Proximal muscle loss Encephalopathy (if severe) / Asterixis Fetor Hepaticus Hepatomegaly / Splenomegaly Gynecomastia / Hypogonadism Spider angiomata (telangiectasias) Palmar erythema Nail changes Anovulation / Hypogonadism Terry Nails Muerke Nails

32 Diagnosing Cirrhosis There are no standard lab tests But certain lab tests do help show poor liver function (INR, albumin) Imaging is typically obtained if cirrhosis is suspected Though still not sensitive or specific to make the diagnosis (so use in context of exam & labs to help support the diagnosis) Start with abdominal US (tells about the appearance of the liver & blood flow w/in portal circulation, less expensive, no contrast or radiation) Liver may appear: small, nodular, increased echogenicity May give clues to portal HTN (dilated portal vein) CT & MRI generally not performed (dye, radiation, cost) Liver biopsy: gold standard (not needed if imaging & clinical picture/labs fit)

33 Other Complications of Liver Disease Portal Hypertension Gastroesophageal Varices Variceal Hemorrhage Ascites SBP Hepatic Encephalopathy Hepatorenal Syndrome Hepatopulmonary Syndrome Portopulmonary HTN HCC Portal Vein Thrombosis Cirrhotic Cardiomyopathy Indicate Decompensated Cirrhosis Risks: Bleeding Infection ETOH Meds Dehydration Constipation Obesity

34 Portal Hypertension & GE Varices Portal Hypertension Leads to alterations in portal venous blood flow MC manifestations are GE varicies, ascities, & HE Portal pressure >12 is generally enough to start causing problems (ascites, varices) If pressure can be reduced to < 12, then ascites will resolve The increased pressure leads to progressive splanchnic vasodilation, which causes a whole host of down stream effects (decreased BP, poor renal perfusion, varices)

35 Portal Hypertension & GE Varices Gastroesophageal Varices Present in 30-60% of patients with cirrhosis at the time of diagnosis Enlarge over time and may spontaneously rupture Tx hemorrhage with Octreotide (vasoconstriction), Antibiotics (Ceftriaxone or Norfloxacin for 5-7 d or until DC), & Endoscopic therapies (band ligation or sclerotherapy) Initiate secondary prophylaxis: nonselective BBs If re-bleeding occurs - consider TIPS Mortality has been reduced to 15-20% with treatments Those with cirrhosis should be screened for varices Positive Screen (lg varices) Primary prophylactic treatment: Non-selectivve BBs (propranolol, nadolol) Reduce HR by 25% or 55-60bpm No further surveillance needed Endoscopic variceal band ligation (if can t take BBs) Requires ongoing surveillance Both reduce hemorrhage by 40% Negative screens (not lg varices) Screen q2-3 yr if no varicies Screen annually if small to medium varicies

36 Ascites & SBP Ascites The most frequent complication of cirrhosis Its secondary to portal hypertension ~50% of patients with compensated cirrhosis get it w/in 10 years All new ascites requires diagnostic paracentesis (cell count, diff, albumin, total protein, & culture) Calculate SAAG S albumin - A albumin SAAG > 1.1 AND Ascites protein < 2.5 Treatment (for CLINICALLY apparent cases): < 2g NaCl/day + diuretics (spironolactone + furosemide, ratio of 100:40 mg/day) +/- large volume paracentesis (+ albumin 8g/ L fluid) Refractory cases: serial paras, TIPs, & liver transplant = portal HTN SBP + fluid culture + Abs PMN >= 250 cells/microl Treatment: 3rd generation cephalosporin (5 d) Albumin (shown to decrease mortality) Stop BB (increases HRS & LOS) MC pathogens: E.Coli, Klebsiella pneumoniae, and pneumococcus Secondary Prophylaxis: Norfloxacin (Bactrim if allergic) Primary Prophylaxis: if low protein ascitic fluid (<1g/dL) and severe liver dysfunction (esp if hospitalized) Mortality has dropped from 50% to 15% Clinically apparent ascites: Abd distension, edema Exceptions: huge salt intake, fluid resuscitated, or Hep B (sincee these have other potential remedies)

37 Hepatic Encephalopathy Disturbance in CNS dysfunction Due to hepatic insufficiency and portosystemic shunting Many hypotheses (low O2, toxin release from injury liver cells, impaired gluconeogenesis) But Ammonia is certainly the big factor at play It is produced by colonic bacteria in the gut during catabolism of nitrogenous sources (proteins, secreted urea) & is reabsorbed from gut and enters circulation via the portal vein Normally a HEALTHY liver clears almost all of it before it enters systemic circulation Increased frequency and severity predict an increased risk of death Need to rule out other causes: metabolic disturbances, infections, meds, intracranial lesions or events Other risks: recent TIPS or large portosystemic shunts (seen on CT imaging) Serum ammonia levels do NOT correlate with stage of encephalopathy (but helpful to evaluate for unexplained confusion) Treatment: focus on reducing excess nitrogen in the gut Lactulose: nonabsorbable disaccharide the decreases absorption of ammonia (goal of 3-4 BMs daily) Oral antibiotics (neomycin and rifaximin): reduce effects of colonic bacteria on ammonia production & are added for refractory cases

38 Hepatorenal Syndrome Portal HTN > arterial vasodilation in splanchnic circulation (due to increased vasodilator production / release) > Systemic vascular Resistance falls > Reduced BP > Activates RAS > Renal Vasoconstriction & reduced renal perfusion > severe reduction in GFR (minimal histo changes) Type I: rapidly progressive (Cr doubles to > 2.5 or Cr clearance drops by 50% to < 20 ml/min/1.73 m2 in < 2 weeks Type II: Is not rapidly progressive & commonly associated with refractory ascites Major Criteria (diagnosis of exclusion): Serum Cr > 1.5 No improvement after 2 days of diuretic withdrawal & volume expansion with albumin(to < 1.5) Absence of septic shock or hypotension No current or recent treatment with nephrotoxins Absence of identifiable parenchymal kidney disease (no significant proteinuria of <500 mg/d, hematuria, ATN, obstruction) Treatment: RCTs have shown improved creatinine with albumin volume expansion Raise BP: norepinephrine (if in the unit) or midodrine (alpha 1 agonist, vasoconstricts) & octreotide (inhibits endogenous vasodilator release to help maintain splanchnic vasoconstriction) Perhaps TIPS (this is a newer indication not our call) Otherwise, Liver transplant still remains the most effective treatment

39 Hepatopulmonary Syndrome & Portopulmonary Hypertension HPS: PPH: Defect in arterial oxygenation due to pulmonary vascular dilation in the setting of cirrhosis and portal hypertension Dyspnea on exertion or at rest is the hallmark symptom Suspect in patients with cirrhosis who develop hypoxemia (po2 < 70) in absence of other causes Microbubble visualization w/in LA after 3-6 cardiac cycles on a contrast enhanced TTE is diagnostic No effective medical therapies Those with arterial PO2 < 60 become high priority candidates for liver transplant Coexisting primary portal HTN + pulmonary HTN Confirmed by RHC Poor prognosis For those with PAPs > 35 to 50, transplant is no longer an option due to increased risk of preoperative death

40 Board Question A 45yro man is admitted for new onset RUQ pain, ascites, fever, and anorexia. History is notable for HTN & alcoholism. Hi only med is HCTZ. On exam, Temp is 100.6F, BP 110/50, HR 92, RR 16. BMI is 24. Spider angiomata are noted on chest and neck. Liver is palpable and tender. + Abd tenderness with flank dullness to percussion. Labs: Alk phos 210, ALT 60, AST 125, Bili 6.5, Cr 1.8 The Maddrey discriminant function score is 36. US discloses coarsened hepatic echo texture, splenomegaly, and moderate to large amount of ascites. Diagnostic para reveals SBP and IV ceftriaxone is started. EGD is notable for small esophageal varices w/o red wale signs and no evidence of recent bleeding. In addition to continuing ceftriaxone and starting albumin, which of the following is the most appropriate treatment? 1. Etanercept 2. Infliximab 3. Pentoxifylline 4. Prednisolone MDF of 32 or greater = severe alcoholic hepatitis. ALL severe cases should get treated. Prednisolone is the preferred treatment unless there are contraindications such as INFECTION, renal failure, or GIB. This guy has SBP. In this case, pentoxifylline is the alternative treatment choice.

41 Hops Water Barley Reinheitsgebot German beer purity law of 1516 Use of rye and wheat were prohibited so that these more valuable grains would be available for baking bread