Tohoku J. exp. Med., 1982. 137, 213-220
`
`Diurnal Fluctuation of Blood Ammonia Levels
`
`in Adult--Type Citrullinemia
`
`YOSHIAKI YAJIMA. TAKASHI HIRASAWA and TAKEYDRI
`SAHi«:ici*
`
`Uli3n.ic of Internal ilalerlicré-ire, Ia'o.lci-Kyorirs-ar (:'e-ne-ml Hospixril.
`Ia.-olci 972 and *l)e;oor£mr.m.t of B*iocliem.*is£-ry. Toke.-i ll-:v.=i':=.-'ei'siI+!y
`Sr:l=.ool of M edict-ne.
`I.-aeiirnro L59-II
`
`I)-iareuil Fluctuation of Blood
`Yi\.Jnui\. Y.. HIRA:-iA\\«‘A. T. and SMIEKI. T.
`Tohoku J. exp. Med"
`lli82,
`.-lmmomli Levels
`in :ld1ill'—Typc
`(.“i'm:lli'ae-nn'o.
`137(2), 213-220 ——A 48-year-old man. who was diagnosed as adult-type
`citrullinemia by quantitat-ive estimation cl‘ urea cycle enzymes in the liver.
`showed a regular nocturnal rise of blood ammuiin level.
`In order to elucidate the
`mechanism of diurnal [fluctuation of blood am monia level. the pu.t.ient was put into
`fasting state for four days. The blood ammonia level rose at the night of the
`first Fasting day even though no food was taken, then it decreased gradually and
`reached the lowest
`level
`in the morning of the third fasting day.
`intravenous
`administration of amino acids mixture under the same starved condition gave rise
`to a significant elevation of blood ammonia level. Based on these results. it was
`concluded that hyperanimoiiemia of adult-type eitrullinemia could result from
`the accumulation of free ammonia which was produced from the catabolism of
`amino acids absorbed from the small intestine and surpassed the urea synthesis
`of defective urea cycle to flood into the blond.
`l1'1li’tl1eI."m(}re.
`the rise of blood
`:i‘m‘rnunia. level at the night. of the first fasting day suggested that
`the circadian
`rhythm of amino acid-trarliohydratc metabolim might supcrimpcse on the process
`mention;-_d a,bm.rc_
`adult-type citrullinemia:
`liyperammoncmia; diurnal
`H iu:tua.t.iori
`
`A 48-year-old man with adult—type citrullinemia has heen described in our
`previous report (Yajima. et al. 1981). He showed repetitive episodes of encephalo-
`pathy and was diagnosed by quantitative estimation of amino acids and urea cycle
`enzymes in the liver.
`In this case, a regular diurnal fluct-nation of the blood
`ammonia level was seen and the drip infusion of gluta.mate—a.rginine mixture and
`oral administration of citrate lowered the blood ammonia level, But
`the liver
`
`function tests of the patient became worse one month after the laparotoiny for
`the evaluation of urea. cycle enzymes and he clinically deteriorated to the state
`of general
`liver failure with jaundice and ascites. He died two months after the
`laparotomy. At the stage of general liver failure, citrate ingestion was iaeifective
`and regular diurnal l'luctua.tion of blood ammonia was no long-_>:er seen.
`
`Received for piililirsaioii. October 5. 1981.
`Dr. Yajima's present address: The Third Department of Internal Medicine. Tohoku
`University School of Medicine. Sendai E18“.
`Elli
`
`
`
`LUPIN EX. 1012
`
`LUPIN EX. 1012
`
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`

`214
`
`Y. Yajima et al.
`
`This paper discusses the mechanism of regular diurnal fluctuation of blood
`ammonia characteristic of this case from the data obtained in a starvation test,
`
`ammonia tolerance test.
`
`intravenous amino acids loading test and variation of
`
`blood ammonia during the period of general liver failure.
`
`Mernon AND S1,-'B.Ir:ers
`
`A case of adult-type eitrullinemia and. as controls. five cases of decompensated live.r
`cirrhosis were studied. Case 1 of control group was a -1ti—_vear-old male who had a mesoeaval
`shunt operation for the esophageal varices and hypersplenism. Case 2 was a 53-year-old
`male in whom hepatic encephalopathy appeared following the rupture of the esophageal
`varices and thereafter encephalopathy of grade 1 to 2 according to Sherloel-c’s classification
`lasted. Case 3 was a fil-year-old female who was a deeompensated cirrhotic patient with a
`triad of ascites. jaundice and encephalopathy and in whom laetuluse administration of 00
`ml at day after the onset of encephalopathy lowered blood ammonia level. Case 4 was a 08-
`year-old female who had intractable aseites refractory to both strict salt restriction and
`the use of potent diuretics during the three-months‘ hospitalization. Case 5 was a 40-
`year-old male who was admitted to our hospital because of aseites and responded well to
`medical treatment. The ascites was not present at the time of blood ammonia determina-
`tion. Blood ammonia was measured by the modified method of Okucla and Fujii (I966)
`(normal range 40-80 gig} 100 ml}.
`
`RESULT
`
`Variation of blood ammonia tenets in ad-alt-type cit-math:-nentia
`
`The efiieet of starvatiloa. To prevent the hyperammonemia. protein intake was
`restricted to less than 50 gr a clay and the clinical course was observed. Symptoms
`of encephalopathy and asterixis occurred at night. The blood ammonia was
`measured four times a day,
`i.e., 9:00 a.m., 2:00 p.n1.. 8:00 p.n1. and 11:00 pm.
`during three consecutive days in order to elucidate the correlation between hyper-
`ammonemia and enceplialopathy.
`It revealed that the level of blood ammonia
`depicted a gentle curve which had its peak between 8:00 p.n1. and 11:00 p.m.
`Blood ammonia. was then measured at 9:00 am. and 8:00 p.m. every day. The
`average of fasting levels was 120:l:38 pg,f100 ml at 9:00 am. and 430:L-T9 ,ug,lI00 ml
`at 8:00 p.m.
`
`Siclnrulion
`
`leverllugml}
`Bloodammonia
`
`
`Days
`
`Fig. 1. Variation of blood ammonia levels during starvation. The night of the first fasting
`day had a rise of blood ammonia level without taking any food, since then it decreased
`gradually to reach the lowest level in the morning of the third day. 0.
`levels at 9:00
`z1.m.; 0.
`levels at 8:00 p.111.
`Second starvation trial was stopped on the third
`fasting day.
`
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`
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`

`

`Diurnal Fluctuation of Blood Ammonia
`
`215
`
`[:1 order to investigate the mechanism of the nocturnal rise of blood ammonia
`level the patient was put into a. fasting state for four days. During the starvation
`period. water. electrolyte and ‘£00 g glucose were supplemented intravenously and
`the lilood ammonia level was rneasurecl at 9:00 a.m. and 8:00 p.m. every day. The
`blood ammonia level rose in the night of the first fasting day, but since then it
`decreased gratlllally and reached the lowest level in the morning of the third fasting
`day.
`But- after the night of the third day the blood ammonia level began to rise
`again. Another starvation trial under the same condition performed a week later
`showed the same result.
`
`The rjfiifrt of i'n.Z-rrwe-nous rid-iai-mistrazilori of ta-as-mo acids. Under the same con-
`dition as the previous two starvation trials, an amino acids mixture was adminis-
`tered intravenously’ in the night of the first and the second day and the morning of
`the third day. The amino acids mixture was a commercially available one which
`was synthesized after
`the constituent oi'
`the human milk.
`500 ml of a 5%
`solution of the amino acids mixture was administered by drip infusion for 2 hr
`and the blood ammonia level was measured immediately after the end of the in-
`fusion.
`In each occasion, the hlood ammonia levels rose considerably by 100-
`
`three
`in decornpensated cirrhotic case {Case 4) with an aseites,
`200 ;zgfl00 ml.
`trials of amino acids infusion in the fasting state in the early mornirtg had no
`influence on the blood ammonia levels.
`
`2’ _.
`
`'3 §
`E 9E K.
`" 3".
`3 "
`2to
`
` 3':3
`
`'00 it
`
`so
`
`O
`
`3
`
`Before
`
`After
`
`Days
`
`Fig. 2. The effect of the intravenous administration of amino acids mixture during the
`starva-t-iori period. Two broken lines inrlicnte starvation trials without amino acids
`ndministmtion.
`«:2. blood ammonia levels after amino acids administra.t.ion.
`
`.~lmm.om'a tel.’-cm'n.c.e test. Ammonium chloride. 0.5 g! 10 kg body weight, was
`loaded orally and blood ammonia was measured every half an hour. Blood amnionia
`had its peak at 60 min after loading and got to the initial value 2 hr later (Fig. 3).
`
`l7rmiu.£-tori of blood rmisincriért feet’! rt‘-uri;'ii.g the stage of general tine? failure. The
`liver function tests of the patient became worse a month after the laparotomy
`for liver biopsy and clinically deteriorated to the state of general liver failure with
`
`3of8
`
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`
`

`

`215
`
`‘I’. Yajima 91- ill.
`
`400 —
`
`NH4Cl (0.5 qr'lO kg 3. w.)
`
`E E
`
`2o
`
`n
`
`.2 E
`3 0
`E 9 200 -
`E ‘I.
`D U-
`U 1O ..
`
`300 —
`
`I00 -
`
`0—*_4:H
`O
`30
`SO
`90
`l2O
`Time l’ min 1
`
`Fig. 3.
`
`.-Immonia tolerance teat.
`
`800
`
`BOO
`
`..—.— intravenous nyperalirnenlafion —.
`
`3
`
`D2D
`
`F;
`3 __
`S
`E 9
`‘E 2;
`13 3}
`
`Fig. 4. V£I.ria.tion of blood ammonia levels in the stage of general liver failure.
`9:00 1'1-.I'n.; 0,
`levels at 8:00 p.1n.
`
`0,
`
`levels at
`
`Days
`
`jaundice and ascites. He was not fed and was maintained with intravenous hyper-
`aliinentation. At
`this stage,
`regular diurnal
`fluctuation of blood ainmonia.
`characteristic of this patient was no longer seen (Fig. 4).
`
`l*’ar1Iotz'on of blood amirionirc level in decompensatecl liver celr-2-120.927.:
`
`In the following five cases, protein intake W3!’-l restricted to less than 50 g a. day.
`As :1 rule, blood ammonia was measured twice a day, 9:00 am. and 8 :00 p.111. except
`Case 1.
`
`A case of mesocmm-l slim;-.t (Case 1}. Blood ammonia measurement was done
`twelve times serially over two (lays. There was no reglllarity olaservcd in the
`variation of the blood armnonia level (Fig. 5).
`
`Cases of encizplialoyiathy.
`
`In Case 2. the variation pattern was no longer diurnal
`
`in Case 3, a trend of slight
`but rather {luctuating with cycle of several days each.
`nocturnal rise of blood ammonia was seen before the onset of encephalopathy but
`the trend became unclear after the onset. (Fig. 6).
`
`4of8
`
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`
`

`

`;
`
`o D
`_s:_ 0
`E T.
`U E‘:
`5ED
`
`300
`
`I00
`
`O
`
`Diurnal
`
`l"1uct.11ation of Blood .'~\mmoni:1
`
`217
`
`Comrol
`
`J
`
`8100
`
`r2200
`
`£600
`
`800
`
`12:00
`
`IE-=00
`
`Hours
`
`Fig. 5. Diurrml lluutuzit-ion of the blond ammonia.
`Int-‘sucava..l nrmatnmnsis.
`
`levels in the t'.irrhntic patient with
`
`2500!: Control 2
`
`200
`
`L00 -
`Encephulopofhy
`0
`300 -
`
`Control 5
`
`
`
`200_
`0 -
`10
`
`0
`300
`
`F Control 4
`
`Encephutopathy
`7
`/
`
`‘ZOO I»
`I00 J’
`0h
`
`Control 5
`
`' O0 -
`5
`
`200 I-
`
`100 I-
`
`O
`I.
`3
`5
`7
`
`Days
`
`___
`
`E O
`
`9“K.
`
`'3:
`“
`E
`
`73
`
`C ‘
`
`.2
`
`E’
`0
`E
`"CI
`E
`to
`
`\-';u~i;.,t.iun nfthe blond zmmmnnin lovvis.
`Fig-_ (3_
`at 9:0!) :L.m.: 0.
`It-vvla at 3:04) pm.
`
`in ti:-tromprfinsuted cirrhotic cases. 0, levels
`
`5of8
`
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`
`

`

`218
`
`Y. Yajima. et.
`
`:1].
`
`blood
`seen in Fig. 6,
`In Cases 4 and 5, as
`Cases without encejifialopathy.
`ammonia levels were lower than the levels of those cases with encephalo_pathy and
`depicted a gentle curve with a cycle of several to ten days.
`
`Disc USBION
`
`The contribution of ammonia to the pathogenesis of hepatic encephalopathy has
`been widely investigated { Walker and Schcnker 1970; Schcnker et- al. 1974). Amino
`acids imbalance (Fischer et al.
`IQT5} and short—chain Fatty acid {Chen et al. 1970;
`Zieve et al. 1974) have recently been proposed as etiological
`factors
`in hepatic
`encephalopathy. Among them. ammonia is the most important in the treatment of
`hepatic encephalopathy in the sense that we can control it to some extent.
`In
`patients with I}01'l3\fl:l-'SySlIv{3IT)lC shunt and experimental animals with hepatic damage
`or Eek fistula, meat intoxication or protein intoxication has been known (Nencki
`et al. 1896; Monguio and Krause 1934). and protein restriction is effective for lower-
`ing the blood ammonia level and improving the clinical course.
`There was no
`report. however. dealing with hepatic encephalopathy which referred to the varia-
`tion of blood ammonia level from the view point of‘ diurnal fluctuation. The case
`with mesocaval shunt, one of the controls, showed no trends of hlood ammonia to
`
`fluctuate diurnally and other four controls of decompensated cirrhosis also did not
`show the regular fluctuation pattern of blood ammonia.
`On the other hand, in the field of congenital hyperammonemia. Batshaw et al.
`(1975)
`reported a case of
`thirteen~year-old female with
`carhamyl phosphate
`synthetase deficiency in which nocturnal rise of" blood ammonia was seen. Nloser
`et al.
`(1967) reported two cases of argininosuccinic aciduria in which the blood
`ammonia levels were normal or slightly elevated in the fasting state but a marked
`elevation occurred postprandially.
`In the fields of aclult—type eitrullinemia, Suzuki
`et al. (1980) reported a case in which the variation of blood animonia. was closely
`associated with food ingestion.
`In our case, the measurement of blood ammonia
`over a two months period revealed rises of blood ammonia level every night even
`when encephalopathy was not seen. These results suggested that postprandial
`elevation, or regular nocturnal rise, of blood ammonia should he a pathognomonic
`sign of the abnorinality in urea cycle.
`Therefore.
`in the hyperalnmoncmia caused by portal-systemic shunt, blood
`for the determination of ammonia need not iiecessarily be sampled in the fasting
`state in the morning and if adult-type citrullinemia is suspected. blood samples must
`be collected postprandially.
`The starvation test, performed to clarify the mechanism of the nocturnal rise
`of blood ammonia, showed a gradual decrease oi" blood ammonia.
`level. supporting
`the hypothesis that orally taken nitrogens are closely associated with the elevation
`of blood ammonia level.
`
`Incidentally. the blood ammonia levels in the night of the first fasting day were
`significantly elevated compared with those in the morning and re—elcvation of
`levels began since the night of the third fasting day. As to the former, it was
`
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`
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`

`Diurnal Fluctuation of Blood Ammonia
`
`219
`
`postulated that nocturnal rise of blood ammonia was not only caused by the meal
`but also can he influenced by the circadian rhythm of amino acid—earbohydr-ate
`metabolism regulated by the circadian rhythm of hormone secretion. The most
`probable explanation of the re-elevation of blood ammonia. since the third day is
`the generation of free ammonia in the catabolism of endogenous amino acids.
`"Intravenous administration of amino acids mixture under the same starved
`
`condition showed :1 reuiarkable elevation of arnmonia in tl1e adult-type citrullinemia
`
`but no effect in a decompensated. cirrhotic patient. And, the ammonia tolerance
`test showed a peak at 80 min after amlnonium ingestion, a little later than in
`cirrhosis.
`llrlurawaki et al.
`(1977)
`reported a case of 23-year-old male with
`ornithine transcarhamylase (OTC) deficiency in which the ammonia tolerance
`test showed a unique curve ahruptly rising at 75 min after loading, which is
`obviously distinct from that seen in cirrhosis. But
`in two cases of adult-type
`OTC deficiency, reported by Short et al. (1973), both of them showed peaks at 30
`min.
`inconsistent with the case reported by Murawaki et al. (1977).
`As regards adult-type citrullinemia. in the case of Suzuki et al. (1980) and the
`case of Yauiauchi et al.
`(1980),
`the results of ammonia tolerance test were
`reported.
`In both of them, ammonia tolerance curves rose slowly until 60 min,
`hut it was not clear \-.=hetl1er the value at 60 min was a. peak value or not because
`
`in general, most of the cirrhotic cases
`the data after 60 min were not presented.
`have their peak values at 15 to 45 min (Conn 1960].
`It may he said that the
`patients with deficiency of urea cycle enzyme have their peaks later than the
`liver cirrhotics. But there is a question in diagnosing the deficiency of urea cycle
`ernzyme from the ammonia tolerance test because some of the cirrhotics have their
`peaks at 60 or 90 min (Ohwada et al. 1977}. On the other hand,
`the intravenous
`amino acids loading test is thought to be a. useful test
`for
`the diagnosis of the
`deficiency of urea cycle enzyme.
`From these data. we proposed the following mechanism for the diurnal fluctua—
`tion of the blood ammonia in our patient: Hyperamnionemia of portal-systemic
`encephalopathy due to liver cirrhosis results from the generation of free ammonia
`by intestinal bacterial flora in the large intestine.
`It takes 4 hr on the average for
`non-digestible nitrogenous source to arrive at the large intestine (Read ct al. 1980)
`and generate free ammonia and 50 hr on the average to be evacuated from the
`rectum [Cummings et al. 1976).
`it Follows. therefore, that the nitrogenous source
`in a meal brings about the rise of blood ammonia. with a time lag of 4 to 50 hr.
`Because of this time lag. regular diurnal fluctuation of blood ammonia associated
`with meal ingestion is not seen in the portal—systemic encephalopathy. On the
`other hand. hyperammonemia of adult-type citrullinemia could result From the
`accumulation of free ammonia which was produced from the cataholism of amino
`
`acids absorbed from the small intestine and surpassed the urea synthesis of defec-
`tive urea cycle to Hood int-o the blood.
`in the night of the first fasting
`FlIrthe'rn1oI.'e. the rise of blood ammonia level
`day smggcsted that the circadian rhythm of amino acid—carhohydrate metabolism
`might supcrimpose the process mentioned ahove.
`
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`
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`
`

`

`220
`
`Y. Yzijirii.-1. et al.
`
`Acknowledgment
`
`We are indebted to Prof. Y. Gate, The Third Department of Internal Medicilie,
`Tohoku University School of Medicine.
`for his valuable advices and em-onragement
`in
`preparing this paper.
`
`References
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`1)
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`3)
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`\Vu|ser, M. (1975) Treatment. of carbamyl phosphate
`Bafshaw, M.. Brusilow. S. 3:.
`Sfnt-llvtase deficiency with ketcanalogues of essential amino acids. New Engl. J.
`JIed.. 292.
`l0H5—ID90.
`Chen. S., Hahadevnn. V. &. Zieve. L. {l9T0) Volatile fatty acids in the breath ofpatielits
`with cirrhosis of the liver.
`J. Lab. din.
`.‘|Ied..
`'75, 622--527.
`Conn. H.(). (1960) Ammonia tolerance in liver disease.
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`.-h'ed., 55. 355-
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`£5 Wiggins, H.S. (I976) Measuremt-.nt of the mean
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`transit time of dietary residue through the human gut-. Gut. 17, 210-218.
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`Monguio, J. & Krause. F. (1934) Uber die Bcdeutung des NH3 Gehaltes des Blut-es fiir
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`and <lemonst.1'a.t-ion of intermit-tent.
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`.1ferl., 42. 9-26.
`Murswal-xi. Y.. Yoshirla. K., Hirsyama. C.. Nakao, T. 3:. Nakaya-. Y. (19771 Inherited
`hyperammonclnia. in adult-.
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`[I966] Direct spect-rophntnmetrica] determination of blood
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`Yajima. Y.. Hirasawa. T. &, Sahel-ti. T. (IQE-ll} Treatment ot':Ldult--type citrullinemia with
`atlrninistration cf citrate. Tofmlsu J. .-=.:c_3J.
`.-h"ed.. 134, 3‘2l~33tI.
`b'_vru:rgism between
`Zieve. F.J.. Zia-ve. L.. Driizziki. W..\l. E: Gilsdorf,
`I-LB. {I974}
`ammonia and fatty acids in the production of coma:
`lmplica-tions for hepatic coma.
`.)'_ Ph.r:.rmr:r:oI. exp.
`'Ni.r-.r.. 191.
`ll|'—]li.
`
`(I974) Hepatic encephalopathy:
`
`8of8
`
`8 of 8
`
`