GASTROENTEROLOGY 1981;81:1025-35
`
`Hypotyrosinemia, Hypocystinemia, and
`Failure to Retain Nitrogen During Total
`Parenteral Nutrition of Cirrhotic
`Patients
`
`DANIEL RUDMAN, MICHAEL KUTNER, JOSEPH ANSLEY,
`ROBERT JANSEN, JACQUES CHIPPONI, and RAYMOND P. BAIN
`Departments of Medicine, Biometry, and Surgery, Emory University School of Medicine
`and the Clinical Research Facility, Emory University Hospital, Atlanta, Georgia
`
`Six patients with gastrointestinal malabsorption
`and 12 with alcoholic cirrhosis received total paren(cid:173)
`teral nutrition for 4 wk. Freamine II, the source of the
`amino acids, is nearly devoid of cystine and tyro(cid:173)
`sine. We monitored daily nitrogen balance and other
`nutritional parameters and 22 plasma amino acids.
`Malabsorbers had a strongly positive nitrogen bal(cid:173)
`ance and improvements in nutritional parameters.
`Plasma amino acids were maintained within or
`above their normal fasting ranges. Eight of 12 cir(cid:173)
`rhotics resembled malabsorbing patients in terms of
`positive nitrogen balance, improved nutritional pa(cid:173)
`rameters, and plasma amino acids. In 4 cirrhotics,
`nitrogen balance remained negative and nutritional
`repletion failed to occur. Plasma cystine and tyro(cid:173)
`sine fell to below 30% of their normal fasting means.
`In 2 of these patients, oral supplements of cystine
`and tyrosine were given during the fifth week of
`parenteral nutrition. Plasma cystine and tyrosine
`were normalized, nitrogen balance became positive,
`and other repletion indicators demonstrated recov(cid:173)
`ery. We conclude that in 4 cirrhotics, repletion was
`blocked by deficiencies of cystine and tyrosine,
`resulting from hepatic inability to synthesize cystine
`from methionine and tyrosine from phenylalanine.
`
`Protein-calorie malnutrition (PCM) is common in
`advanced cirrhosis (1-3) and is often difficult to
`Received February 9, 1981. Accepted July 6, 1981.
`Address reprint requests to: Daniel Rudman, M.D. , Director,
`Clinical Research Facility, Emory University School of Medicine,
`1364 Clifton Road, NE, Atlanta, Georgia 30322.
`This study was supported by U.S. Public Health Service Grant
`AM15736 and by General Clinical Research Center Public Health
`Grant 5M01R00039.
`© 1981 by the American Gastroenterological Association
`0016-5085/81/121025-11$02.50
`
`correct because of anorexia. Total parenteral nutri(cid:173)
`tion (TPN) provides a new approach to this problem.
`Total parenteral nutrition infuses into the right atri(cid:173)
`um each day about 3 L of a solution containing 3000
`calories and 2-5 times the recommended daily al(cid:173)
`lowances of nonessential and essential amino acids,
`minerals, and vitamins (4). This method has promot(cid:173)
`ed nutritional repletion in PCM caused by several
`types of chronic illness (short bowel syndrome,
`gastrointestinal obstruction, enterocutaneous fistu(cid:173)
`las, inflammatory bowel disease, chronic pancreati(cid:173)
`tis, and catabolic states following burns and trauma)
`(5), as evidenced by positive N, P, and K balances,
`and by improvement in serum albumin, creatinine
`excretion, and anthropometric indices. However,
`cirrhotic patients have abnormal amino acid metabo(cid:173)
`lism, as indicated by distorted plasma aminogram
`(6-8), hyperammonemia (9), mercaptanemia (10),
`and diminished urea production (11-13). In cirrhot(cid:173)
`ic patients, therefore, the amino acid requirements
`may be different than those in normal individuals.
`Accordingly, it is uncertain whether the TPN solu(cid:173)
`tions in current use will replete emaciated cirrhotic
`patients as effectively as these solutions replete other
`types of undernourished individuals.
`In this study we administered TPN for 4-5 wk to
`12 patients with alcoholic cirrhosis and PCM. Nutri(cid:173)
`tional repletion was evaluated by N balance, body
`weight (BW), triceps skinfold (TSF), midarm muscle
`area (MAMA), urinary creatinine/height ratio, and
`serum albumin concentration. The plasma amino(cid:173)
`gram was also monitored because it reflects the
`adequacy of the subject's amino acid intake (14-18),
`although it is also influenced by alcoholism and
`liver disease (19). In order to study N balance for 4-5
`
`Eton Ex. 1060
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`
`

`

`1026
`
`RUDMAN ET AL.
`
`GASTROENTEROLOGY Vol. 81, No.6
`
`Table 1. Clinical Features of the Patients Who Were Observed During 4-5 Weeks of TPN
`
`Average age (SD)
`Sex: M/F
`Duration since diagnosis (yr)
`Diagnosis
`Massive resection of small intestine
`Regional ileitis
`Alcoholic cirrhosis
`Ascitesa
`o
`1
`2
`Child's score (42)
`A
`B
`C
`
`a Graded as described in methods.
`
`Malabsorption
`
`48.3 (5.6)
`4/2
`1-24
`
`Cirrhosis
`
`46.9 (7.1)
`8/4
`3-16
`
`Cirrhotic
`(subgroup 1)
`
`44.8 (6.8)
`5/3
`4-15
`
`Cirrhotic
`(subgroup 2)
`
`51.3 (6.3)
`3/1
`3-16
`
`3
`3
`
`6
`
`12
`
`2
`6
`4
`
`8
`
`1
`4
`3
`
`1
`7
`o
`
`4
`
`1
`2
`1
`
`o
`4
`o
`
`wk with constant intake of nutrients, and without
`need to use insulin or diuretics (which complicate
`interpretation of plasma aminograms and N bal(cid:173)
`ances), patients with diabetes mellitus, hyponatre(cid:173)
`mia, severe ascites, impaired renal function, or a
`history of hepatic encephalopathy were excluded.
`For comparative purposes the same study was car(cid:173)
`ried out in 6 patients with PCM caused by gastroin(cid:173)
`testinal malabsorption.
`Methods
`
`Subjects
`Guidelines for entry of patients into this study were
`the following: (a) urinary creatine/height ratio and MAMA
`below 75% of standard; (b) in the alcoholic patients,
`biopsy-proven micronodular cirrhosis;
`(c)
`in malab(cid:173)
`sorbers, fecal fat >25 g/day from a daily diet having 100
`g offat/day; (d) no past history or present clinical evidence
`of hepatic encephalopathy; (e) fasting venous plasma NH3
`concentration <80 JLg/dl; (f) serum Na+ concentration
`135-145 mEqlL; (g) normal fasting and 2-h postprandial
`blood sugar concentrations; (h) no past or present insulin
`treatment; (i) normal serum creatinine level; and (j) ascites
`not more severe than 2, when graded as follows: 0, no
`ascites; 1, positive puddle sign; 2, frank dullness to the
`anterior axillary line with shifting dullness; 3, frank asci(cid:173)
`tes without eversion of the umbilicus; 4, frank ascites with
`eversion of the umbilicus.
`Thirty-one emaciated patients (8 with malabsorption, 23
`with cirrhosis) were chosen for study. In 2 of the 8
`malabsorbers TPN was discontinued because of fever. In 2
`of 23 cirrhotics amino acid content was reduced because of
`encephalopathy, and in another 5, insulin was begun and
`carbohydrates were reduced because of glycosuria. Total
`parenteral nutrition was stopped because of fever in 2
`patients; diuretics were started and the NaCI content of the
`
`solution was reduced in 2 patients because midabdominal
`circumference had increased by more than 20%. The 2
`mal absorbers and 11 cirrhotics who had TPN modified or
`discontinued are not considered further in this report. The
`clinical data of the 18 remaining patients are given in
`Tables 1 and 2.
`
`Experimental Design
`All patients were offered a diet furnishing 100 g of
`protein, 250 g of carbohydrate, and 80 g of fat per day.
`Initial evaluation comprised history, physical examina(cid:173)
`tion, and the laboratory and nutritional data bases shown
`in Table 2. Blood chemistries were obtained at 8 AM after
`an overnight fast on two different days. Neurologic status
`was graded by clinical examination and by electroenceph(cid:173)
`alograph, according to the criteria of Parsons-Smith et al.
`(20). Methods for the component tests in the data bases,
`and normal ranges for each test, are. given in Table 3.
`The patients then began a 4 or 5 wk course of TPN,
`during which they took only water by mouth. Insertion
`and care of the subclavian catheter and preparation of the
`TPN solution have been described elsewhere (21). The
`solution's composition is given in Table 4; it was infused
`at a constant rate around the clock. During the first 3 days,
`rate of infusion was progressively increased to 3000
`ml . (24 h)-l . (70 kg ideal body wt)-l (IBW, calculated
`according to Ref. 22) and remained unchanged thereafter.
`In order to supply essential fatty acids, 500 ml of Intrali(cid:173)
`pid· (70kgIBW) . day-l [containing550cal· (70kgIBW)-l
`day-l] was substituted for an equicaloric quantity of
`glucose on the fourth day of each week. During weeks 2, 3,
`4, and (in 2 cirrhotic patients) 5, we continued to monitor
`the metabolic and nutritional variables listed in Tables 2
`and 3. The methods by which these measurements were
`made are shown in Table 3. The indicated blood chemis(cid:173)
`tries were obtained at 8 AM while TPN continued. During
`each day of TPN urine was tested for glucose, midabdom-
`
`Eton Ex. 1060
`2 of 11
`
`

`

`a Values represent average (SD) (for n, Table 3). Amino acid concentrations are expressed as % of their normal fasting means. These means are the midpoints of the normal fasting ranges listed in
`
`Table 3. Ascites was graded as described in Methods.
`
`5.3 (1.0)
`
`6.0 (0.7)
`
`6.8 (0.9)
`
`115 (26)
`139 (29)
`132 (23)
`153 (31)
`119 (31)
`197 (55)
`119 (25)
`186 (19)
`213 (51)
`186 (65)
`106 (15)
`175 (44)
`102 (19)
`136 (29)
`320 (54)
`121 (25)
`198 (70)
`115 (19)
`174 (34)
`131 (22)
`116 (21)
`
`0(0)
`35 (1)
`68 (10)
`45 (5)
`74 (7)
`42 (4)
`1.0 (0.2)
`38 (8)
`150 (43)
`
`0.9 (0.3)
`
`143 (31)
`
`3.4 (0.6)
`11.8 (0.5)
`35.8 (1.3)
`54.4 (3.8)
`
`Week 4
`
`100 (4)
`140 (23)
`125 (19)
`143 (20)
`107 (13)
`200 (62)
`114(15)
`194 (31)
`193 (56)
`215 (81)
`99 (8)
`182 (54)
`105 (11)
`130 (28)
`310 (69)
`115(17)
`187 (25)
`131 (20)
`196 (33)
`142 (29)
`99 (19)
`0(0)
`35 (1)
`64 (10)
`46 (7)
`70 (8)
`34 (4)
`1.0 (0.2)
`40 (8)
`130 (17)
`
`105 (19)
`122 (16)
`114 (12)
`135 (17)
`98 (9)
`
`152 (23)
`103 (12)
`173 (13)
`177 (31)
`176 (45)
`102 (29)
`153 (31)
`24 (16)
`124 (27)
`298 (53)
`102 (16)
`174 (35)
`130 (26)
`169 (24)
`123 (19)
`98 (20)
`0(0)
`34 (1)
`61 (10)
`40 (5)
`67 (8)
`34 (6)
`1.1 (0.3)
`34 (4)
`
`151 (18)
`
`0.9 (0.3)
`
`0.8 (0.2)
`
`61 (10)
`47 (16)
`102 (21)
`55 (22)
`76 (24)
`67 (8)
`42 (11)
`53 (21)
`53 (13)
`51 (16)
`57 (19)
`57 (16)
`58 (15)
`61 (14)
`111 (22)
`59 (13)
`70 (18)
`87 (14)
`86 (21)
`59 (20)
`57 (17)
`0(0)
`34 (1)
`59 (11)
`37 (6)
`63 (9)
`37 (6)
`0.9 (0.2)
`32 (8)
`139 (51)
`
`0.8 (0.3)
`
`150 (20)
`
`145 (18)
`
`142 (27)
`
`3.1 (0.5)
`12.9 (0.7)
`34.6 (1.5)
`51.1 (2.8)
`
`2.7 (0.5)
`12.3 (1.0 )
`32.8 (1.6)
`47.9 (2.9)
`
`2.6 (0.6)
`12.3 (1.0)
`32.0 (2.2)
`46.0 (3.2)
`
`Week 2
`Week 3
`Malabsorption (n = 6)
`
`Pre
`
`Week 4
`
`Cirrhotic subgroup 2 (n = 4)
`
`Week 3
`
`Week 2
`
`Pre
`
`Week 4
`
`Week 3
`
`Week 2
`
`Cirrhotic subgroup 1 (n = 8)
`
`Pre
`
`Table 2. Summary of Clinical, Nutritional, and Amino Acid Data Before and During 4 Weeks of TPN°
`
`-0.1 (0.7)
`101 (9)
`183 (16)
`170 (9)
`287 (79)
`98 (15)
`566 (79)
`
`25 (7)
`
`173 (11)
`176 (23)
`554 (135)
`48 (50)
`183 (27)
`52 (49)
`168 (9)
`420 (36)
`94 (21)
`332 (42)
`174 (17)
`329 (51)
`268 (63)
`57 (29)
`2.8 (0.5)
`42 (2)
`52 (10)
`82 (26)
`50 (6)
`77 (11)
`
`94 (14)
`200 (36)
`165 (23)
`315 (70)
`105 (24)
`631 (54)
`29 (14)
`186 (21)
`193 (39)
`607 (129)
`53 (43)
`205 (16)
`54 (48)
`190 (10)
`474 (58)
`98 (15)
`336 (10)
`176 (18)
`372 (81)
`290 (59)
`62 (36)
`2.0 (0.8)
`42 (4)
`52 (12)
`79 (25)
`50 (7)
`67 (5)
`
`1.4 (0.1)
`
`1.4 (0.1)
`
`91 (41)
`299 (145)
`3.6 (1.0)
`
`102 (16)
`
`2.1 (0.3)
`16.3 (3.1)
`25.8 (0.5)
`54.4 (4.6)
`
`74 (15)
`
`278 (121)
`2.9 (0.9)
`
`118 (18)
`
`2.4 (0.2)
`14.6 (2.0)
`28.0 (0)
`50.6 (5.0)
`
`-0.6 (0.2) +0.2 (0.2)
`95 (11)
`132 (33)
`156 (20)
`265 (30)
`97 (10)
`565 (103)
`
`46 (23)
`172 (9)
`182 (14)
`533 (139)
`
`52 (25)
`196 (41)
`56 (29)
`
`164 (8)
`458 (25)
`
`89 (8)
`
`305 (25)
`183 (35)
`323 (68)
`241 (47)
`63 (36)
`1.3 (0.5)
`40 (4)
`53 (11)
`74 (25)
`49 (6)
`62 (15)
`1.0 (0.2)
`54 (7)
`224 (82)
`
`2.2 (0.8)
`
`136 (23)
`
`2.8 (0.2)
`13.5 (0.9)
`31.0 (0.7)
`47.8 (5.2)
`
`135 (48)
`122 (10)
`109 (29)
`95 (22)
`101 (29)
`171 (30)
`161 (62)
`60 (10)
`63 (10)
`238 (40)
`88 (20)
`62 (13)
`104 (14)
`102 (22)
`274 (59)
`102 (15)
`113 (25)
`116 (11)
`114 (34)
`101 (17)
`83 (19)
`1.0 (0.8)
`38 (3)
`53 (11)
`72 (25)
`50 (6)
`59 (15)
`0.9 (0.2)
`54 (15)
`225 (87)
`
`2.1 (0.7)
`
`152 (18)
`
`5.9 (1.2)
`
`6.2 (0.9)
`
`116 (26)
`180 (43)
`144 (43)
`236 (45)
`102 (21)
`314 (38)
`105 (17)
`222 (50)
`282 (73)
`388 (64)
`105 (15)
`216 (44)
`95 (22)
`158 (26)
`444 (85)
`97 (15)
`347 (98)
`181 (52)
`297 (50)
`190 (35)
`110 (20)
`
`0.5 (0.5)
`36 (2)
`64 (12)
`65 (21)
`71 (10)
`75 (13)
`1.0 (0.1)
`50 (18)
`155 (31)
`
`1.5 (0.6)
`
`167 (26)
`
`108 (19)
`168 (43)
`138 (32)
`221 (24)
`99 (31)
`305 (34)
`115 (20)
`208 (48)
`268 (69)
`384 (46)
`92 (13)
`197 (27)
`99 (17)
`156 (23)
`454 (65)
`96 (19)
`358 (53)
`181 (59)
`300 (43)
`190 (36)
`102 (17)
`0.9 (0.4)
`37 (3)
`60 (12)
`62 (20)
`67 (10)
`76 (14)
`1.1 (0.2)
`62 (22)
`190 (49)
`
`1.8 (0.6)
`
`153 (23)
`
`6.4 (1.5)
`97 (16)
`157 (33)
`127 (30)
`195 (13)
`109 (14)
`282 (45)
`109 (14)
`203 (47)
`251 (70)
`381 (60)
`99 (13)
`186 (29)
`99 (18)
`145 (29)
`426 (59)
`90 (17)
`324 (45)
`177 (51)
`266 (48)
`165 (24)
`91 (16)
`1.3 (0.7)
`38 (4)
`57 (13)
`59 (20)
`64 (10)
`67 (7)
`1.0 (0.2)
`73 (30)
`247 (49)
`
`2.3 (0.7)
`
`140 (27)
`
`124 (40)
`126 (19)
`105 (24)
`107 (31)
`101 (20)
`146 (39)
`190 (60)
`60 (16)
`75 (48)
`148 (34)
`102 (24)
`57 (16)
`97 (30)
`142 (39)
`297 (118)
`107 (24)
`128 (28)
`140 (18)
`96 (31)
`100 (27)
`82 (19)
`1.3 (0.7)
`39 (4)
`54 (12)
`56 (19)
`61 (10)
`66 (17)
`1.0 (0.2)
`85 (35)
`254 (97)
`
`2.3 (0.8)
`
`141 (33)
`
`2.8 (0.2)
`3.0 (0.5)
`12.4 (2.1)
`13.0 (1.5)
`34.5 (1.6)
`31.9 (1.3)
`54.7 (10.1) 44.9 (5.4)
`
`2.4 (0.5)
`15.3 (2.0)
`31.0 (2.6)
`50.0 (11.0) 51.3 (11.1) 51.3 (10.1)
`
`2.8 (0.5)
`13.9 (1.6)
`33.8 (1.6)
`
`2.6 (0.4)
`14.8 (1.6)
`31.6 (2.6)
`
`~N [g. (70 kg IBW)-I . day-I]
`Plasma arginine
`Plasma tryptophan
`Plasma histidine
`Plasma lysine
`Plasma ornithine
`Plasma phenylalamine
`Plasma tyrosine
`Plasma leucine
`Plasma isoleucine
`Plasma methionine
`Plasma cystine
`Plasma valine
`Plasma a-aminobutyric acid
`Plasma alanine
`Plasma glycine
`Plasma citrulline
`Plasma proline
`Plasma glutamine
`Plasma serine
`Plasma threonine
`Plasma taurine
`Ascites (grade)
`Abdominal circumference (cm)
`Creatininelheight ratio (% of std)
`TSF (% of std)
`MAMA (% of std)
`Plasma NH3 (J-Lg/dJ)
`Serum creatinine (mg/dJ)
`Serum SGOT (UldJ)
`Serum LDH (U/dJ)
`Serum bilirubin (mg/dJ)
`Serum cholesterol (mg/dl)
`Serum albumin (g/dJ)
`Prothrombin time (s)
`Hematocrit (%)
`Body wt (kg)
`
`Eton Ex. 1060
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`

`

`1028
`
`RUDMAN ET AL.
`
`GASTROENTEROLOGY Vol. 81, No.6
`
`Table 3. Data Base for Monitoring Patients Before and During TPNa
`
`Test
`
`Hematocrit
`Prothrombin time
`Serum albumin
`Serum cholesterol
`Serum bilirubin
`Serum LDH
`Serum SGOT
`Serum creatinine
`Venous plasma NH3
`EEG
`Neurologic grade
`MAMA
`
`TSF
`
`24-hour urine creatininelheight ratio
`
`Daily N balance
`Plasma taurine
`Plasma threonine
`Plasma serine
`Plasma glutamine
`Plasma proline
`Plasma glycine
`Plasma alanine
`Plasma citrulline
`Plasma a-aminobutyric acid
`Plasma valine
`Plasma cystine
`Plasma methionine
`Plasma isoleucine
`Plasma leucine
`Plasma tyrosine
`Plasma phenylalanine
`Plasma ornithine
`Plasma lysine
`Plasma histidine
`Plasma tryptophan
`Plasma arginine
`
`Reference
`
`Normal range in
`absolute units
`
`Normal range, as
`percent of
`normal mean
`
`43
`44
`45
`46
`47
`48
`48
`49
`50
`20
`20
`51
`
`51
`
`51
`
`21
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`23
`52
`23
`
`35%-48%
`10-14 s
`3.7-4.8 g/dl
`154-312 mgldl
`0.3-1.0 mg/dl
`52-227 Ulml
`11-48 Ulml
`0.4-1.1 mgldl
`21-44 fLg/dl
`0
`N
`Male, 50.9 cm2
`Female, 42.8 cm2
`Male, 12.5 mm
`Female, 16.5 mm
`Male, 8.66 mg/cm;b
`Female, 6.01 mglcmb
`-0.6 to + 1.7 g' (70 kg IBW)-l . day-l
`20-80 fLM
`102-190 fLM
`68-160 fLM
`517-773 fLM
`99-379 fLM
`152-320 fLM
`241-597 fLM
`19-55 fLM
`10-42 fLM
`178-326 fLM
`42-75 fLM
`20-44 fLM
`48-120 fLM
`106-214 fLM
`42-102 fLM
`47-83 fLM
`29-101 fLM
`136-260 fLM
`67-111 fLM
`29-90 fLM
`37-171 fLM
`
`80%-120%
`
`69%-130%
`
`85%-115%
`
`40%-160%
`69%-130%
`59%-140%
`80%-119%
`41%-158%
`64%-135%
`57%-142%
`51%-148%
`38%-161%
`70%-129%
`71%-128%
`62%-137%
`57%-142%
`66%-133%
`58%-141%
`72%-127%
`44%-155%
`68%-131%
`75%-124%
`50%-150%
`41%-158%
`
`a Each test was performed twice a week except for N balance and 24-h urine creatinine/height ratio, which were done every day. Methods
`and normal ranges are given for each procedure. Normal range (2 SD around the mean) is based on data of 26 normal subjects 25-54 yr
`old. Ascites were monitored daily by inspection (see Methods) and by measurement of abdominal circumference midway between
`xyphoid and symphysis pubis in the supine patient before arising. b For a male 5'9" and for a female 5'4".
`
`inal circumference was measured, and a neurologic ex(cid:173)
`amination was performed.
`Venous plasma amino acids were measured by ion
`exchange chromatography according to Benson et al. (23).
`Blood was collected in a heparinized tube, chilled to O°C,
`spun at 5000 g for 10 min at 4°C, and stored for up to 4 wk
`at -80°C. * Before analysis the plasma was thawed and
`deproteinized by addition of an equal volume of 8%
`sulfosalicylic acid. Nitrogen balance was calculated as: N
`
`*When plasma is stored at -80°C, the concentrations of cystine
`and other amino acids remain unchanged, within the limits of
`experimental error, for up to 8 mo (26). Storage at -20°C,
`however, causes the loss of cystine and glutamine.
`
`intake minus (urinary N + fecal N + change in total body
`urea N) (24). Total body urea N was calculated as BUN
`(mglL) times total body water (L) (24). Total body water
`was determined at 2-4 wk-intervals according to Foy and
`Schneider (25).
`Midway through the course of the study we found that
`some cirrhotic patients, during TPN, had developed defi(cid:173)
`ciencies of cystine or tyrosine, of which little or none was
`present in the TPN solution, and had failed to retain N.
`This led to a modification of the experimental design. In
`the last portion of the study those cirrhotic patients who
`had retained little or no N during weeks 2, 3, and 4 then
`received a fifth week of TPN with oral supplements of
`cystine (0.3 g tid) and tyrosine (0.3 g tid).
`
`Eton Ex. 1060
`4 of 11
`
`

`

`December 1981
`
`HYPERALIMENTATION IN CIRRHOSIS
`
`1029
`
`Table 4. Contents of One Liter of the TPN Solution
`
`Dextrose
`Amino acids
`Isoleucine
`Leucine
`Lysine
`Phenylalanine
`Methionine
`Cysteine
`Threonine
`Tryptophan
`Valine
`Alanine
`Arginine
`Glycine
`Histidine
`Proline
`Serine
`Ornithine
`Na
`K
`Cl
`P
`Ca
`Mg
`Fe
`Zn
`Mn
`Cu
`Fluoride
`Iodide
`Molybdenum
`Selenium
`Ascorbic acid
`Vitamin A
`Vitamin D
`Thiamine
`Riboflavin
`Pyridoxine
`Niacinamide
`Pantothenic acid
`Vitamin E
`Folic acid
`Vitamin K
`Vitamin BI2
`
`200 g
`33.3 g
`2.1 g (16.0 mmol)
`2.7 g (20.6 mmol)
`2.7 g (18.5 mmol)
`1.7 g (10.3 mmol)
`1.6 g (10.7 mmol)
`<0.2 g «0.83 mmol)
`1.2 g (10.0 mmol)
`0.45 g (2.2 mmol)
`1.9 g (16.2 mmol)
`2.3 g (25.8 mmol)
`1.1 g (6.3 mmol)
`6.3 g (84.0 mmol)
`0.8 g (5.1 mmol)
`3.3 g (28.6 mmol)
`1.7 g (16.1 mmol)
`3.3 g (19.6 mmol)
`25 mEq
`40 mEq
`20 mEq
`7mmol
`5 mEq
`6 mEq
`25 fLmol
`10 fLmol
`20 fLmol
`2.5 fLmol
`25 fLmol
`0.5 fLmol
`0.07 fLmol
`0.1 fLmol
`150 mg
`1100 IU
`110IU
`7 mg
`3.3 mg
`5 mg
`33 mg
`7.5 mg
`11.5 IU
`0.3 mg
`0.3 mg
`33 fLg
`
`R~sults
`
`Patients with Malabsorption
`
`The data are summarized in Table 2. (a) Nitro(cid:173)
`gen balances averaged + 6.1 g' (70 kg IBW)-l day-l
`during weeks 2-4 of TPN. (b) Gain in BW averaged
`0.42 kg· (70 kg IBW) day-I. (c) Urinary creatinine/
`height ratio, MAMA, and TSF initially averaged
`59%,63%, and 37% of standard. All these indicators
`of peM improved steadily during TPN, reaching the
`following levels 4 wk later: 68%, 74%, and 45% of
`
`standard, respectively. (d) The fasting plasma amino
`acid pattern obtained before TPN showed a general(cid:173)
`ized hypoaminoacidemia; average values for many
`plasma amino acids were below the normal fasting
`range. After TPN was instituted the amino acid
`profile changed markedly. No average amino acid
`concentration was below, while many were now
`above, the normal fasting range. The elevated amino
`acids were in general those that were present in the
`TPN solution in highest concentration (Table 4). (e)
`No untoward clinical events occurred except for
`mild leg edema and tachycardia.
`
`Cirrhotic Patients
`
`(a) Inspection of the N balance separated the
`into 2 subgroups (Table 2).
`cirrhotic patients
`Throughout TPN the 8 patients in subgroup 1 re(cid:173)
`tained N to the same degree as the malabsorption
`cases [average +6.2 g' (70 kg IBW)-I . day-I]. In
`contrast the 4 patients of subgroup 2 had N balances
`close to zero [average -0.2 g' (70 kg IBW)-I . day-I].
`Weeks 2, 3, and 4 produced similar results. These
`two subgroups are analyzed separately in the sec(cid:173)
`tions below, and in Tables 2 and 5. (b) Gain in BW
`averaged 0.25 kg· (70 kg IBW)-I . day-I in subgroup
`1 and was significantly higher (p < 0.05) in subgroup
`2 [average 0.47 kg . (70 kg IBW)-I . day-I]. (c) In
`subgroup 1 the pre-TPN values for creatinine/height
`ratio, MAMA, and TSF were 54%, 61%, and 56% of
`standard, respectively. After week 4 these values had
`improved significantly to 64%, 71% and 65% of
`standard. In subgroup 2 the pre-TPN values were
`similar to subgroup 1: 53%, 50%, and 72% of stan(cid:173)
`dard, respectively. Unlike subgroups 1, however,
`creatinine/height ratio and MAMA failed to improve
`during 4 wk of TPN. Triceps skinfold, on the other
`hand, widened to 82% of standard. (d) In subgroup 1
`albumin rose from 2.4 g/dl before treatment to 3.0 g/
`dl after treatment. The corresponding values in sub(cid:173)
`group 2 showed a decline in albumin from 2.8 to 2.1
`g/dl. (e) During 4 wk of TPN in subgroup 1, hemato(cid:173)
`crit, bilirubin, SGOT, LDH, cholesterol, and pro(cid:173)
`thrombin time improved significantly (p < 0.05). In
`contrast these liver status indicators all deteriorated
`significantly in subgroup 2. (f) In subgroup 1, the
`pre-TPN fasting plasma amino gram showed valine
`and leucine levels below their normal fasting ranges.
`During TPN all plasma amino acids were either
`within their normal fasting ranges (taurine, a-ami no(cid:173)
`butyric acid, cystine, tyrosine, ornithine, arginine,
`citrulline) or above them (threonine, serine, gluta(cid:173)
`mine, proline, glycine, alanine, valine, methionine,
`isoleucine, leucine, phenylalanine, lysine, histidine,
`tryptophan). In subgroup 2, the average pre-TPN
`
`Eton Ex. 1060
`5 of 11
`
`

`

`1030
`
`RUDMAN ET AL.
`
`GASTROENTEROLOGY Vol. 81. No. 6
`
`Table 5. Comparison of Data for the Three Groups of Subjects Before TPN. and During the Fourth Week of TPN Q
`
`Cirrhotic subgroup 1
`vs. subgroup 2
`
`Cirrhotic subgroup 1
`vs. malabsorption
`
`Cirrhotic subgroup 2
`vs. malabsorption
`
`Pre-TPN
`
`Week 4
`ofTPN
`
`Pre-TPN
`
`Week 4
`of TPN
`
`Pre-TPN
`
`Week 4
`of TPN
`
`BW
`Hematocrit
`Prothrombin time
`Serum albumin
`Serum cholesterol
`Serum bilirubin
`Serum LDH
`Serum SGOT
`Serum creatinine
`Plasma NH3
`MAMA
`TSF
`Urinary creatininelheight ratio
`Abdominal circumference
`Ascites grade
`Plasma taurine
`Plasma threonine
`Plasma serine
`Plasma glutamine
`Plasma proline
`Plasma citrulline
`Plasma glycine
`Plasma alanine
`Plasma a-aminobutyric acid
`Plasma valine
`Plasma cystine
`Plasma methionine
`Plasma isoleucine
`Plasma leucine
`Plasma tyrosine
`Plasma phenylalanine
`Plasma ornithine
`Plasma lysine
`Plasma histidine
`Plasma tryptophan
`Plasma arginine
`aN
`t
`a Arrows indicate p < 0.05 for a comparison. For comparison of cirrhotic subgroup 1 vs. subgroup 2. t signifies subgroup 1 was
`significantly greater than subgroup 2; for comparison of subgroup 1 vs. malabsorption. t means the former was significantly greater
`than the latter; for cirrhotic subgroup 2 vs. malabsorption. t indicates the former was significantly greater than the latter.
`
`t
`~
`t
`t
`~
`~
`L
`L
`
`t
`
`t
`t
`t
`
`t
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`t
`
`t
`
`t
`t
`t
`t
`t
`t
`
`t
`t
`
`t
`t
`
`t
`
`t
`t
`
`t
`t
`~
`
`t
`t
`t
`t
`t
`L
`t
`
`t
`t
`t
`
`t
`
`t
`
`t
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`
`t
`t
`
`t
`t
`
`t
`t
`
`plasma amino acid profile resembled that in sub(cid:173)
`group 1. During TPN all but 4 amino acids behaved
`as in subgroup 1 by rising into or above their normal
`fasting ranges. However, average concentrations of
`cystine and tyrosine declined below 30% of their
`normal fasting means throughout weeks 2, 3, and 4.
`A similar reduction affected taurine and a-aminobu(cid:173)
`tyric acid, which are metabolic products of methio(cid:173)
`nine-cystine metabolism. Neither homocystine, cys(cid:173)
`tathionine, nor homoserine, additional products of
`sulfur amino acid metabolism, was detectable in the
`plasma or urine of subgroup 2 before or during TPN.
`(g) Ascites progressively improved in subgroup 1
`during TPN and worsened in subgroup 2. (h) Neuro-
`
`logic status and blood NH3 remained unchanged
`during TPN in both subgroups.t
`
`Fifth week of TPN: Effect of Cystine/Tyrosine
`Supplements in Two Cases of Cirrhotic
`Subgroup 2
`
`In 2 patients of subgroup 2 TPN was contin(cid:173)
`ued for 1 more week with the addition of 0.3 g
`cystine and 0.3 g tyrosine by mouth at 9 AM, 3 PM,
`and 9 PM (see Table 6). The 8 AM plasma aminogram
`
`tTwo cirrhotics who developed encephalopathy were excluded
`from the study, as noted under Methods.
`
`Eton Ex. 1060
`6 of 11
`
`

`

`December 1981
`
`HYPERALIMENTATION IN CIRRHOSIS
`
`1031
`
`Table 6. Effects of Tyrosine and Cystine Supplements in Two Cirrhotics of Subgroup 2. Each Value is an Average (for n,
`see Table 3). Plasma Amino Acids are Expressed as Percent of Their Normal Fasting Means
`
`Case No. 1
`
`Case No.2
`
`Week 2
`
`Week 3
`
`Week 4
`
`Week 5
`
`Week 2
`
`Week 3
`
`Week 4
`
`Week 5
`
`BW (kg)
`Hematocrit (%)
`Prothrombin time (s)
`Serum albumin (g/dl)
`Serum cholesterol (mg/dl)
`Serum bilirubin (mg/dl)
`Serum LDH (Ulml)
`Serum SGOT (Ulml)
`Serum creatinine (mg/dl)
`Plasma NH3 (J-Lg/dl)
`MAMA (% of std)
`TSF (% of std)
`Creatinine/height ratio
`(% of std)
`Abdominal circumference (em)
`Ascites (grade)
`Plasma taurine
`Plasma threonine
`Plasma serine
`Plasma glutamine
`Plasma proline
`Plasma citrulline
`Plasma glycine
`Plasma alanine
`Plasma u-aminobutyrie acid
`Plasma valine
`Plasma cystine
`Plasma methionine
`Plasma isoleucine
`Plasma leucine
`Plasma tyrosine
`Plasma phenylalanine
`Plasma ornithine
`Plasma lysine
`Plasma histidine
`Plasma tryptophan
`Plasma arginine
`6N
`
`46.5
`30.0
`13.0
`2.7
`130
`2.3
`286
`47
`1.0
`77
`40
`97
`
`45
`38
`
`57
`276
`290
`208
`300
`87
`493
`159
`37
`176
`34
`688
`185
`162
`77
`481
`83
`224
`154
`182
`107
`-~9
`
`49 .7
`28.0
`13.0
`2.4
`114
`3.5
`289
`66
`1.4
`64
`40
`103
`
`41
`40
`2
`39
`263
`395
`189
`349
`86
`478
`180
`30
`207
`28
`712
`200
`210
`36
`598
`92
`380
`178
`196
`87
`-0.5
`
`aSignificantly different from weeks 2, 3, and 4 (p < 0.05).
`
`53 .8
`25.5
`15.5
`2.0
`95
`4.6
`274
`62
`1.2
`62
`42
`106
`
`43
`41
`3
`42
`242
`333
`172
`308
`122
`408
`165
`26
`176
`14
`693
`160
`160
`34
`530
`81
`250
`168
`202
`100
`-0.4
`
`52.0
`28.0
`13.0
`2.4
`115
`4.1
`280
`51
`0.9
`70
`46
`110
`
`49
`39
`2
`127u
`278
`330
`160
`257
`109
`370
`190
`135a
`169
`157a
`557
`151
`205
`160a
`438
`115
`265
`138
`225
`82.0
`+6.5 U
`
`55.2
`31 .5
`14.5
`2.8
`168
`1.1
`124
`50
`0.7
`47
`54
`90
`
`47
`44
`2
`58
`217
`417
`141
`274
`85
`486
`164
`39
`182
`51
`580
`183
`174
`29
`667
`84
`289
`182
`228
`102
`-0.8
`
`57.6
`28.0
`11.5
`2.3
`143
`1.6
`152
`59
`1.3
`70
`54
`92
`
`47
`46
`3
`45
`272
`473
`197
`326
`120
`393
`190
`30
`181
`38
`590
`166
`197
`15
`711
`109
`303
`174
`252
`78
`0.2
`
`60 .1
`26.5
`13.0
`2.0
`125
`2.2
`158
`51
`1.4
`77
`56
`98
`
`48
`49
`3
`48
`307
`398
`155
`290
`97
`396
`156
`28
`155
`38
`605
`153
`173
`17
`683
`104
`288
`165
`187
`106
`0.1
`
`58.2
`30.0
`12.0
`2.4
`149
`2.0
`150
`50
`1.0
`84
`59
`100
`
`53
`47
`2
`126u
`283
`417
`184
`313
`117
`399
`190
`143a
`153
`154a
`557
`179
`205
`142a
`600
`104
`333
`166
`232
`86
`+5 .1"
`
`showed a rise of cystine, tyrosine, taurine, and a(cid:173)
`amino-butyric acid into or above their normal fasting
`ranges. Simultaneously, N balance rose to average
`+5.8 g' (70 kg IBW)-I . day- I. Substantial improve(cid:173)
`ment occurred during the week in hematocrit, albu(cid:173)
`min, bilirubin, cholesterol, SGOT, LDH, prothrom(cid:173)
`bin time, MAMA, and urinary creatinine/height
`ratio.
`
`Statistical Analysis of the Differences
`Between Cirrhotic Subgroups 1 and 2, and
`the Malabsorption Group
`
`Repeated measures analysis of variance was
`used to analyze between group comparisons that are
`
`summarized in Table 5. (a) Before TPN cirrhotic
`subgroup 1 did not differ significantly from sub(cid:173)
`group 2 on any variable except for plasma methio(cid:173)
`nine (increased in subgroup 2). Four weeks later,
`however, the clinical and nutritional indicators were
`significantly worse in subgroup 2. The only signifi(cid:173)
`cant differences in the aminogram were lower values
`of cystine, tyrosine, taurine, and a-aminobutyric
`acid in subgroup 2, and the higher values of methio(cid:173)
`nine and phenylalanine. (b) Cirrhotic subgroup 1
`differed from malabsorbers before treatment, most
`liver tests being abnormal and most plasma amino
`acids being higher. After 4 wk most of these differ(cid:173)
`ences had largely resolved except for higher levels of
`several plasma amino acids. (c) Cirrhotic subgroup 2,
`
`Eton Ex. 1060
`7 of 11
`
`

`

`1032
`
`RUDMAN ET AL.
`
`GASTROENTEROLOGY Vol. 81, No.6
`
`before TPN, differed from the patients with malab(cid:173)
`sorption in these respects: elevated bilirubin; wider
`TSF; and higher values for proline, glycine, u-amino(cid:173)
`butyric acid, methionine, tyrosine, phenylalanine,
`tryptophan, and arginine. In the fourth week of TPN
`subgroup 2 had deteriorated compared with malab(cid:173)
`sorbers, with significantly higher values for methio(cid:173)
`nine, phenylalanine, serine and lysine, and signifi(cid:173)
`cantly lower values for cystine, tyrosine, taurine,
`and u-aminobutyric acid.
`
`Discussion
`In the emaciated patients with malabsorption
`the initial plasma aminogram showed a general(cid:173)
`ized hypoaminoacidemia. During TPN this profile
`changed. The plasma levels of those amino acids
`present in the TPN solution rose above their normal
`fasting ranges and averaged 100%-300% of their
`normal fasting means, and levels of the other amino
`acids rose to approximately their normal fasting
`means. While the plasma aminogram showed correc(cid:173)
`tion of hypoaminoacidemia, progressive nutritional
`repletion occurreq as indicated by strongly positive
`N balance, by rising albumin, hematocrit, and uri(cid:173)
`nary creatininelheight ratio, and by expanding
`MAMA and TSF.
`Repletion of the starved subject requires an ade(cid:173)
`quate supply of all the naturally occurring amino
`acids at the ribosomal sites of protein synthesis
`(27,28). In normal adults the diet need furnish only
`the 8 essential amino acids (leucine, isoleucine,
`valine, methionine, phenylalanine, tryptophan, thre(cid:173)
`onine, lysine), provided enough N is available to
`synthesize the 12 nonessentials (serine, glycine, ala(cid:173)
`nine, tyrosine, cystine, glutamic acid, aspartic acid,
`histidine, arginine, glutamine, asparagine, proline)
`(29,30). When the diet provides insufficient quanti(cid:173)
`ties of an essential amino acid its concentration in
`fasting and in postprandial plasma tends to decline
`below the normal fasting range (14-18). The fact that
`all plasma amino acids in malabsorbers remained at
`or above their mean fasting normal concentrations
`throughout TPN suggests that adequate amounts of
`all amino acids were available. The substantial N
`retention supports this interpretation.
`In the 8 patients of cirrhotic subgroup 1 the degree
`and quality of repletion were similar to those of the
`patients with small intestinal disease, and no plasma
`amino acid concentration was below its normal
`fasting range during the course of TPN. But in the 4
`cases of subgroup 2 repletion of the lean body mass
`did not occur, as evidenced by little or no retention
`of N, and by failure of albumin, urinary creatinine/
`height ratio, and MAMA to improve. Subgroup 2
`exhibited a characteristic plasma aminogram pattern
`
`not seen in cirrhotic group 1 or in the malabsorption
`group: decline below patients' normal fasting ranges
`in the levels of tyrosine, cystine, taurine, and u(cid:173)
`aminobutyric acid. The daily N balance during TPN
`in the entire cirrhotic group was related to the
`plasma aminogram (Figure 1). When the plasmq
`amino acids remained within or above their normal
`fasting ranges (subgroup 1) aN averaged + 6.2 g' (70
`kg IBW) . day-I, but when cystine or