Case Discussion      A 55-year-old woman had been diagnosed as having chronic hepatitis C virus (HCV) infection for 10 years and HCV-related liver cirrhosis, Child-Pugh criteria B, for which she received regular follow-up as an outpatient for 2 year. Ten days prior to the admission, she started to suffer from fever, headache, myalgia, generalized weakness and whitish productive cough. She sought medical attention at a local clinic where common cold was diagnosed and acetaminophen and medications for cough and sputum were prescribed. However, 6 days prior to the admission, she experienced decrease of urine output and deterioration of renal function was found at a local clinic; blood urea nitrogen and serum creatinine were 40 mg/dl and 2.6 mg/dl, respectively. Therefore, she was referred to our emergence service where acute renal failure was suspected and she was admitted for further management. She did not recall taking any medicines that might be nephrotoxic recently.      Upon admission, she had clear consciousness but appeared acutely ill. Her blood pressure was 122/68 mmHg, pulse rate was 88 beats per minute, respiration was 20 breaths per minute, and body temperature was 36.8oC. The pulse oximeter showed SpO2 95% while she was breathing ambient air. The conjunctiva was pink and the sclera was icteric. Lungs were symmetrically expanded with basal crackles at the lower lung fields. The heart rhythm was regular and no cardiomegaly was detected. Shifting dullness was detected on abdominal examination. Mild to moderate pitting edema of the lower extremities was noted. Palmar erythema and spider nevi were also noted. No lymphadenopathy was found at the neck, axillary and inguinal regions. < Laboratory and Image Study > 1. Complete blood count and differential count Date WBC (K/μL) Hgb (g/dL) Hct (%)  Plt (K/μL) Band (%) Seg (%) Eos (%) Baso (%) Lym (%) 3 months prior to the admission 4.5 10.1 30.6 135 Not available (N/A) N/A N/A N/A N/A day 1 of hospitalization 10.82  9.8 28.3 132 1 80 0.3 0.3 10 day 7 9.65 9.5 27.9 130 N/A N/A N/A N/A N/A day 14 8.49 10.2 33.2 134 0 75 0.2 0.3 13.6 Prothombin time (PT)：prolongation <4 seconds 2. Biochemistry Date BUN (mg/dl) Cre (mg/dl) Na (mmol/l) K (mmol/l) AST (U/l) ALT (U/l) Bil (T) mg/dL Albumin (g/dl) Glucose (mg/dl) 3 months prior to the admission 22 1.4 138 3.8 46 76 2.1 3.5 N/A day 1 of hospitalization 44 2.8 133 5.4 52 85 N/A 3.3 120 day 7 59 4.5 128 5.0 N/A N/A 2.2 N/A N/A day 14 50 4.0 132 4.3 40 72 N/A N/A N/A day 21 33 1.9 136 4.3 42 69 2.0 N/A N/A 3. Urine analysis Date Appearance Specific gravity pH Protein (mg/dl) Glucose Ketone Occult blood 3 months prior to the admission Tea color, clear 1.010 6.5 -- -- -- -- day 1 of hospitalization Tea color, clear 1.013 6.5 -- -- -- -- day 10 Tea color, clear 1.011 6.8 <150 -- -- -- Date Urobilinogen Bilirubin RBC WBC Epithelial cells Cast Bacteria 3 months prior to the admission 0.1 + 1-5 <10 1-3 -- -- day 1 of hospitalization 0.1 + -- 10 -- -- -- day 10 0.1 + 1-5 <5 -- -- -- Urine Na：<10 mEq; serum osmolality：282 mOsm/kg water; urine osmolality：340 mOsm/kg water 4. CXR：Normal heart size; mildly blunted costo-pleural angles of bilateral lungs. 5. Renal sonography： Bilateral parenchymal renal disease without hydronephrosis; normal kidney size; and mild to moderate ascites. 6. Serology：NA < Course and Treatment >       Upon admission, she was treated with diuretics. Her daily urine volume was less than 1000 ml after admission. The abdominal sonography excluded the possibility of post-renal cause of acute renal failure. Because of the continuously deteriorating renal function, inadequate intravascular volume was suspected to be contributory, and, therefore, diuretics was discontinued followed by infusion of 1500 ml of plasma expander. However, the renal function did not improve and volume expansion worsened her leg edema. Based on the clinical presentations and laboratory findings, hepatorenal syndrome was suspected, for which she received terlipressin, intermittent infusion of plasma expander and low-dose diuretics (spironolactone and furosemide). Her renal function improved and urine output increased after 3 weeks of hospitalization. She was then discharged and followed up at the outpatient clinic. < 病例分析 >      因fluid loss或sequestration，如ascites，而進一步引起reanl failure在臨床上並不少見，而在住院的肝硬化病患中，約有20%會產生acute renal failure (現稱acute kidney injury, AKI)。臨床上當creatinine從原先指數而快速上升0.3 mg/dL或1.5倍以上時，即可定義為acute renal injury。其中，在肝硬化病患常見的acute renal injury，以prerenal azotemia (volume-responsive prerenal AKI)、acute tubular necrosis及 hepatorenal syndrome (HRS)為主。HRS是在慢性肝病病患發生renal injury時對此一症候群的通稱，多發生在advanced chronic liver disease，但偶爾也發生在急性或猛爆性肝炎的病患。約有40% 帶有ascites的肝硬化病患在其自然病史進行中會發生HRS。HRS的病患其腎臟的組織學檢查是正常的，而通常在肝臟移植後，其腎臟功能會恢復。目前對HRS的致病機制仍不是很清楚，但較被接受的理論是肇因於全身性血流動力學的異常：HRS病患的血流動力學表現為心輸出上升(increased cardiac output)，動脈壓偏低(low arterial pressure)及周邊血管阻力下降(reduced systemic vascular resistance)。雖然心輸出上升，但是由於動脈壓偏低及體液蓄積血管外(ascites及周邊水腫)，進而誘發腎臟血管收縮及血管擴張系統的異常，而產生腎臟衰竭。臨床上HRS分成兩型，雖然致病機制類似，但表現及預後卻大不相同。第一型HRS以快速進展且對液體補充沒有反應的寡尿性(oliguric)腎衰竭為表現，最常由spontaneous bacterial peritonitis (SBP)所引發。但即使已經以抗生素控制了感染，但仍有25%的SBP病患會發生HRS。若無治療，第一型HRS病患的平均存活時間少於兩星期，而事實上大部分的第一型HRS病患在發生腎衰竭後十週內死亡。第二型HRS則多發生在仍保有部份肝功能的病患，其腎功能的喪失則較為緩和，但這些病患的ascites通常對利尿劑的反應不佳(diuretic-resistant)，而其平均存活時間為3至6個月，雖然比第一型HRS長的多，但仍比同樣肝硬化有ascites的病患但沒有腎臟衰竭的病患短。臨床上HRS的診斷是靠臨床症狀為主，實驗室檢驗為輔 (表一)。臨床表現主要是以liver cirrhosis的症狀為主，伴隨有尿量減少及腎功能惡化。本例中的病患本身有liver cirrhosis，因不明原因導致尿量減少及腎功能惡化，住院後的繼續惡化或許跟diuretics的使用有關，但在停藥及輸液治療後並未改善。另外病史也排除了感染及nephrotoxic drugs的使用，再加上實驗數據的輔助，因此診斷為HRS (參看表一)。雖然HRS的診斷須排除超音波檢查有parenchymal renal disease，而此病患的renal ultrasonography顯示有parenchymal renal disease，因此似乎不合診斷標準(表一)，但要說明的是，parenchymal renal disease在renal ultrasonography是屬於相當籠統及主觀的影像診斷，其實並不能依此就絕對排除HRS的診斷。關於HRS的治療方面，最理想且根本的方法為肝臟移殖，但由於過長的等待時間，因此病患多在移殖前死亡，此外在此類病患手術本身也導致相當高的術前、術後死亡率，不過一旦成功，三年存活率可到60%。另外transjugular intrahepatic portosystemic shunt (TIPS)也被報告過有效，但並沒有太多病人因為HRS接受此類治療。至於藥物治療方面則以血管收縮劑為主，由於HRS起初的血流動力學變化是以splanchnic circulation的血管擴張為主，因此使用血管收縮劑反而可以避免活化內生性的血管收縮激素或賀爾蒙，進而防止惡化。此類血管收縮劑藥物如vasopressin V1 receptors agonist (ornipressin 及terlipressin)，somatostatin analogues (octreotide)及alpha-adrenergic agonists (midodrine)(表二 )。 < References >  Hepatology. 2008;48(6):2064-77 Int J Artif Organs. 2009;32(3):133-40 Nephron Physiol. 2008;109(4):p73-9. eMedicine 繼續教育考題 1. (D) 有關hepatorenal syndrome (HRS)臨床上的特徵，不包括以下那一項？ A 全身性血流動力學的異常 B 預後大多不好 C 診斷以臨床症狀為主，實驗室檢驗為輔 D 只在慢性肝病病患發生 2. (C) 若一有ascites的肝硬化病患出現“快速”的腎功能惡化，下列何種原因較不常見？ A Pre-renal azotemia B Acute tubular necrosis C Crescentic glomerulonephritis D Drug-induced 3. (D) 當肝硬化病患出現第一型的HRS時，其最常次發於？ A Hepatoencephalopathy B Severe jaundice C Esophageal variceal bleeding D Spontaneous bacterial peritonitis (SBP) 4. (C) 臨床上HRS的診斷是靠臨床症狀為主，實驗室檢驗為輔，有關診斷HRS下列何者不正確？   A 尿量減少及腎功能惡化 B 無休克或細菌感染 C 輸液1.5 L後，腎功能可改善 D 無嚴重蛋白尿 5. (B) 若病患先前並無腎臟疾病，當發生HRS時腎臟的病理表現多為? A Cresentic formation B Normal C Mesangial hyperplasia D Interstitial inflammatory cells infiltration 6. (C) 對於HRS最好的治療方法為？ A Kidney transplantation B Transjugular intrahepatic portosystemic shunt (TIPS) C Liver transplantation D Vasoconstrictor therapy 答案解說 (D) Hepatorenal syndrome (HRS)是在慢性肝病病患發生renal injury時對此一症候群的通稱．多發生在advanced chronic liver disease，但偶爾也發生在急性或猛爆性肝炎的病患。目前對HRS的致病機制仍不是很清楚，但較被接受的理論是肇因於全身性血流動力學的異常。臨床上HRS的診斷是靠臨床症狀為主，實驗室檢驗為輔 (表一)。大部分的第一型HRS病患在發生腎衰竭後十週內死亡。第二型HRS的平均存活時間為3至6個月。 (C) 在肝硬化病患常見的acute renal injury以prerenal azotemia (volume-responsive prerenal AKI)，acute tubular necrosis及 hepatorenal syndrome (HRS)為主，但是仍須根據病史及檢驗排除其他診斷。 (D) 第一型HRS以快速進展且對液體補充沒有反應的寡尿性腎衰竭為表現，最常由spontaneous bacterial peritonitis (SBP)所引發。但即使已經以抗生素控制了感染，但仍有25%的SBP病患會發生HRS。 (C) 請參考表一 之Major criteria。 (B) HRS的病患其腎臟的組織學檢查是正常的。 (C) 關於HRS的治療方面，最理想且根本的治療為肝臟移殖。